An integrated purification method of high purity (r)-3-aminobutanol

Abstract

The application discloses an integrated purification method of high-purity (R)-3-aminobutanol, and belongs to the technical field of purification of pharmaceutical chemical intermediates, and comprises the following steps: membrane separation is performed on crude product reaction liquid containing (R)-3-aminobutanol to remove macromolecular impurities, and the permeate is collected; the pH value of the permeate is adjusted, and an adsorption unit filled with a chiral molecular imprinting adsorbent is introduced to selectively adsorb (S)-3-aminobutanol isomers and polar impurities, and the effluent after adsorption is collected; the effluent is concentrated to obtain a concentrate; the concentrate is added with a ternary composite solvent for recrystallization, and then solid-liquid separation and drying are performed to obtain (R)-3-aminobutanol products. The process is simple in operation, does not use dangerous reagents, and the solvent can be recycled and reused; the chemical purity of the product is greater than or equal to 99.5%, the optical purity ee value is greater than or equal to 99.8%, the recovery rate is greater than or equal to 92%, and the process is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical intermediate purification technology, specifically an integrated purification method for high-purity (R)-3-aminobutanol. Background Technology

[0002] (R)-3-aminobutanol is a key intermediate in the synthesis of the anti-AIDS drug dulutegravir and the anti-tumor drug 4-methylcyclophosphamide. It can also be derived into β-lactams for the synthesis of penicillin antibiotics. Currently, the market supply of (R)-3-aminobutanol is tight, and there is an urgent need to develop safe and efficient purification processes to support its large-scale production.

[0003] However, existing purification technologies for (R)-3-aminobutanol have several significant drawbacks that make it difficult to meet market demands for high-quality products:

[0004] 1. Chemical resolution method, such as the mandelic acid resolution method used in patent application CN110668958A: This method has high resolving agent costs, complex subsequent processing procedures, easy residues of resolving agent in the product, and the content of isomers is difficult to control effectively (often >0.5%), which cannot meet the strict quality requirements of dolutegravir for intermediates;

[0005] 2. Recrystallization with single / binary solvents, such as the use of acetone-ethanol mixed solvent in patent application CN106748816A: This results in poor improvement in the optical purity of the product (ee value ≤ 99%), and the yield is low, often below 85%.

[0006] 3. Dependence on hazardous solvents: Some synthesis processes (such as patent application CN110683960A) use high-risk reagents such as sodium hydride. Solvent recovery is difficult in subsequent processing and a large amount of waste is generated, causing serious environmental pollution.

[0007] 4. Poor adaptability: Most existing processes are only for crude products from a single source (such as only applicable to biocatalysis or only applicable to chemical synthesis), and cannot take into account the mainstream chemical synthesis route of (R)-3-aminobutyric acid reduction by sulfuric acid / sodium borohydride. In addition, the total impurities are difficult to control (often >1.5%).

[0008] Therefore, there is an urgent need to develop a safe, economical, and widely applicable purification method for (R)-3-aminobutanol, and to improve the purity and yield of (R)-3-aminobutanol products. Summary of the Invention

[0009] The purpose of this invention is to provide an integrated purification method for high-purity (R)-3-aminobutanol to solve the problems mentioned in the background art.

[0010] To achieve the above objectives, the present invention provides the following technical solution:

[0011] An integrated purification method for high-purity (R)-3-aminobutanol includes the following steps:

[0012] Membrane separation pretreatment: The crude reaction solution containing (R)-3-aminobutanol is subjected to membrane separation to remove macromolecular impurities and the permeate is collected;

[0013] Chiral molecular imprinted adsorption: Adjust the pH of the permeate and pass it through an adsorption unit filled with chiral molecular imprinted adsorbent to selectively adsorb (S)-3-aminobutanol isomers and polar impurities, and collect the effluent after adsorption.

[0014] Ternary composite solvent recrystallization: The effluent is concentrated to obtain a concentrate; a ternary composite solvent is added to the concentrate for recrystallization, followed by solid-liquid separation and drying to obtain (R)-3-aminobutanol product; the ternary composite solvent includes isopropanol, methyl acetate and water.

[0015] Furthermore, the membrane separation uses an ultrafiltration membrane for classification; the material of the ultrafiltration membrane is selected from one or more of polyethersulfone, polysulfone, and polyvinylidene fluoride, and its pore size is 50-200 nm.

[0016] Furthermore, the membrane separation operates at a pressure of 0.1-0.3 MPa, a temperature of 25-35°C, and a target product rejection rate of ≤2%.

[0017] Furthermore, the chiral molecularly imprinted adsorbent is prepared by bulk polymerization using (R)-3-aminobutanol as a template molecule, methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a crosslinking agent.

[0018] Furthermore, the preparation method of the chiral molecularly imprinted adsorbent includes the following steps:

[0019] The template molecule, functional monomer, and crosslinking agent are mixed in a molar ratio of 1:(4-6):(15-20), an initiator is added, and a polymerization reaction is carried out at 60-70℃. The resulting polymer product is pulverized, sieved, extracted, and dried to obtain a chiral molecularly imprinted adsorbent.

[0020] Furthermore, the initiator is azobisisobutyronitrile, and its dosage is 1%-2% of the total mass of the template molecule, functional monomer and crosslinking agent; the extraction is carried out by Soxhlet extraction with a mixture of methanol and acetic acid, and the volume ratio of methanol to acetic acid is (8.5-9.5):(0.5-1.5).

[0021] Furthermore, the adsorption unit is a chromatography column; the operating conditions for the chiral molecular imprint adsorption are: adjusting the pH of the permeate to 7.5-8.5, the adsorption temperature to 20-30℃, and the flow rate to 1-3 BV / h.

[0022] Furthermore, in the ternary composite solvent, the volume ratio of isopropanol, methyl acetate, and water is (6-8):(3-1):1.

[0023] Furthermore, the mass ratio of the ternary composite solvent to the concentrate is (3-5):1; the recrystallization adopts a gradient cooling crystallization method, specifically as follows: after holding at 60-70℃ for 1-2 hours, the temperature is lowered to 20-40℃ at a rate of 4-6℃ / h, and then lowered to 0-5℃ at a rate of 1-3℃ / h, and crystallized at this temperature for 4-6 hours; the mother liquor obtained from crystallization is subjected to vacuum distillation to recover the ternary composite solvent, and the recovered ternary composite solvent is recycled for the recrystallization step.

[0024] Furthermore, the crude product reaction solution is derived from a bio-enzyme catalytic process or a chemical synthesis process; the chemical synthesis process is the reduction of (R)-3-aminobutyric acid in an organic solvent by acid and borohydride; the mass fraction of (R)-3-aminobutanol in the crude product reaction solution is 30%-60%, and the optical purity ee value is 85%-95%; the chemical purity of the (R)-3-aminobutanol product is ≥99.5%, the optical purity ee value is ≥99.8%, and the total impurity content is ≤1.0%.

[0025] The integrated purification method for high-purity (R)-3-aminobutanol provided by this invention features simple operation, no use of hazardous reagents, and recyclable solvents. It also significantly improves product purity and yield, and is adaptable to crude products from various sources, making it suitable for large-scale industrial production and effectively alleviating market supply shortages. Specifically, this invention offers the following advantages compared to existing technologies:

[0026] 1. Wide adaptability: It can process crude biocatalysts and crude chemically synthesized products of (R)-3-aminobutyric acid reduced by sulfuric acid / sodium borohydride, covering mainstream production routes;

[0027] 2. Quality meets standards: The product has a chemical purity of ≥99.5%, an ee value of ≥99.8%, isomers of ≤0.15%, total impurities of ≤1.0%, and no residual solvents, meeting the intermediate requirements for high-end drugs such as dulutegravir;

[0028] 3. Safe and economical: No hazardous reagents such as sodium hydride are used throughout the process; solvent recovery rate is ≥90%; and the amount of waste gas, wastewater, and solid waste is reduced by more than 30%.

[0029] 4. Excellent yield: The overall yield is ≥92%, which is much higher than existing processes (mostly ≤85%), and can significantly increase production capacity;

[0030] 5. Easy to scale up: All operating units (ultrafiltration, adsorption, crystallization) are mature industrial technologies, with low equipment investment, suitable for large-scale production of tens of thousands of tons. Attached Figure Description

[0031] Figure 1 This is a schematic flowchart of an integrated purification method for high-purity (R)-3-aminobutanol provided in an embodiment of the present invention. Detailed Implementation

[0032] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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 of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0033] like Figure 1 As shown, in one embodiment of the present invention, to address the problems of existing purification processes such as the use of hazardous solvents, insufficient product purity, and low yield, an integrated purification method for high-purity (R)-3-aminobutanol is provided, comprising the following steps:

[0034] S1. Membrane Separation Pretreatment: The crude reaction solution containing (R)-3-aminobutanol is passed through an ultrafiltration membrane system for membrane separation, which can efficiently remove bacterial cells, proteins, cell debris, or large molecular impurities such as polymers in the chemically synthesized crude product. The permeate is collected. The crude reaction solution is derived from a bio-enzyme catalytic process or a chemical synthesis process. The chemical synthesis process involves the reduction of (R)-3-aminobutyric acid in an organic solvent by acid (such as sulfuric acid) and borohydride. The initial mass fraction of (R)-3-aminobutanol in the crude reaction solution is... The purity is 30%-60%, and the optical purity ee value is 85%-95%; the ultrafiltration membrane material is selected from one or more of polyethersulfone, polysulfone, and polyvinylidene fluoride, and its pore size is 50-200nm; the membrane separation operating pressure is 0.1-0.3MPa, the temperature is 25-35℃, and the rejection rate of the target product (R)-3-aminobutanol is ≤2%, which can provide a clean feed liquid for subsequent adsorption steps, prevent (R)-3-aminobutanol from being lost with macromolecular impurities, and avoid product loss caused by traditional centrifugation and filtration methods.

[0035] S2. Chiral molecularly imprinted adsorption: Adjust the pH of the permeate to 7.5-8.5 and pass it into an adsorption unit (such as a chromatography column) filled with chiral molecularly imprinted adsorbent at a flow rate of 1-3 BV / h. Control the column temperature at 20-30℃ to selectively adsorb (S)-3-aminobutanol isomers. This can increase the ee value of the raw material from 85%-95% to over 99.5%, while removing trace amounts of polar impurities (such as unreacted (R)-3-aminobutyric acid, borate, etc.) to ensure that the isomer content is ≤0.15%. Collect the effluent after adsorption.

[0036] The chiral molecularly imprinted adsorbent is prepared by bulk polymerization using (R)-3-aminobutanol as a template molecule, methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a crosslinking agent. The specific steps include:

[0037] The template molecule, functional monomer, and crosslinking agent are mixed in a molar ratio of 1:(4-6):(15-20), and an initiator (such as azobisisobutyronitrile, the amount of which is 1%-2% of the total mass of the template molecule, functional monomer, and crosslinking agent) is added. The polymerization reaction is carried out at 60-70℃ for 12-16h. The obtained polymer product is pulverized, passed through a 200-300 mesh sieve, extracted by Soxhlet extraction (the extractant is a mixture of methanol and acetic acid, the volume ratio of methanol to acetic acid is 8.5:1.5-9.5:0.5, the extraction time is 8-12h), and vacuum dried (drying temperature is 45-55℃, vacuum degree is ≤-0.09MPa, drying time is 6-8h) to obtain a chiral molecularly imprinted adsorbent. The adsorbent has an adsorption selectivity coefficient of ≥50 for (S)-3-aminobutanol, and the content of (S)-3-aminobutanol isomers in the effluent after adsorption is ≤0.15%. Comparative experiments have verified that its adsorption effect is significantly better than that of adsorbents prepared using other functional monomers (such as acrylic acid and acrylamide) or crosslinking agents (such as divinylbenzene and trimethylolpropane triacrylate).

[0038] S3. Recrystallization with ternary composite solvent: The above effluent is concentrated under reduced pressure at 45-55℃ and -0.08 to -0.09 MPa until no solvent distillation occurs, yielding a concentrate. A ternary composite solvent is added to the concentrate, followed by heating to dissolve and recrystallize (using a gradient cooling crystallization method, the specific procedure is as follows: hold at 60-70℃ for 1-2 hours, then cool to 20-40℃ at a rate of 4-6℃ / h, then cool to 0-5℃ at a rate of 1-3℃ / h, and hold for crystallization for 4-6 hours). After solid-liquid separation (such as filtration), the product is vacuum dried at 40-50℃ (vacuum). High-purity (R)-3-aminobutanol product was obtained by applying a solution with a pressure ≤ -0.09 MPa. The mass ratio of the ternary composite solvent to the concentrate was (3-5):1. The ternary composite solvent was a mixture of isopropanol, methyl acetate, and water in a volume ratio of (6-8):(3-1):1. By adjusting the solvent polarity and hydrogen bonding, the solubility of (R)-3-aminobutanol showed a significant change with temperature: high solubility at 60-70℃, ensuring complete product dissolution; a sharp drop in solubility at 0-5℃, with a crystallization rate ≥90%, and no solvent residue in the product. The key indicators of the final (R)-3-aminobutanol product met the following requirements: chemical purity ≥99.5%, optical purity (ee value) ≥99.8%, total impurity content ≤1.0%, and no detectable residual solvent, conforming to the quality standards for pharmaceutical intermediates.

[0039] It should be noted that the above method may also include a solvent recovery step: the mother liquor obtained from crystallization in step S3 is subjected to vacuum distillation at 55-60℃ and -0.08 to -0.09MPa to recover the ternary composite solvent, with a recovery rate of ≥90%. The recovered ternary composite solvent is recycled for recrystallization, which effectively reduces production costs, and the purity of the product is not affected within 3 cycles.

[0040] Unless otherwise specified, all raw materials used in the following embodiments are commercially available products and can be purchased through commercial channels. The invention will be described in detail below through specific embodiments in practical applications.

[0041] The product testing methods are as follows: Gas chromatography (KB-624 quartz capillary column 60m×0.32mm×1.8μm, FID detector temperature 280℃, injection port temperature 250℃, column temperature program: 50℃ for 6 min → 10℃ / min ramp to 220℃ for 5 min, split ratio 20:1) was used to determine chemical purity and residual solvents; HPLC (X-Bridge C) was used to determine chemical purity and residual solvents. 18 The column was used to determine the ee value and isomer content using a mobile phase of 0.1% triethylamine water (pH adjusted to 3 with phosphoric acid) - methanol = 60:40 and a detection wavelength of 340 nm.

[0042] Example 1: This example provides a method for purifying crude biocatalysts, as detailed below:

[0043] S1. Take 10L of crude (R)-3-aminobutanol reaction solution prepared by bio-enzyme catalysis (initial mass fraction 45%, ee value 90%, containing bacterial / protein impurities), pass it into a 100nm pore size polyethersulfone ultrafiltration membrane system, control the operating pressure at 0.2MPa and temperature at 30℃, collect 9.2L of permeate, and the (R)-3-aminobutanol rejection rate is 1.8%;

[0044] S2. First, prepare a chiral molecularly imprinted adsorbent. The adsorbent is prepared by mixing the template molecule (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate in a molar ratio of 1:5:18. Add 1.5% (by mass) of azobisisobutyronitrile (AIBN) of the total mass of the template molecule (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate. Polymerize at 65℃ for 14 h, pulverize through a 250-mesh sieve, and extract with methanol-acetic acid (9:1 volume ratio) using a Soxhlet extractor for 10 h. Dry under vacuum at 50℃ for 7 h. Adjust the pH of the permeate to 8.0 with 0.1 mol / L NaOH, and pass it through a chromatography column packed with 2 L of the above adsorbent. Control the column temperature at 25℃ and the flow rate at 2 BV / h. Collect 9.0 L of effluent. The ee value is found to be 99.6%, and the (S)-isomer content is 0.12%.

[0045] S3. The effluent was concentrated under reduced pressure at 50℃ and -0.08MPa to 1.5kg concentrate. 4.5kg of ternary composite solvent (isopropanol: methyl acetate: water = 7:2:1) was added, and the mixture was heated to 65℃ and stirred for 1.5h to dissolve. The temperature was then gradually decreased: the plastic was cooled to 30℃ at a rate of 5℃ / h, and then cooled to 3℃ at a rate of 2℃ / h and kept at that temperature for 5h to crystallize. After filtration, the product was dried under vacuum at 40℃ and -0.09MPa to obtain 0.41kg of product.

[0046] Product testing: Chemical purity 99.7%, ee value 99.9%, (S)-isomer 0.08%, total impurities 0.3%, residual solvent not detected, recovery rate 92.3%. Solvent recovery: 3.8 kg of solvent was recovered from the crystallization mother liquor by distillation at 55℃ and -0.09 MPa, with a recovery rate of 93.5%.

[0047] Example 2: This example provides a method for purifying crude (R)-3-aminobutyric acid reduced product in chemical synthesis, as detailed below:

[0048] S1. Take 8 L of crude reaction solution (initial mass fraction 50%, ee value 88%, containing borate / polymer impurities) obtained by reducing (R)-3-aminobutyric acid in tetrahydrofuran with sulfuric acid / sodium borohydride, and pass it through a 150 nm pore size polyethersulfone ultrafiltration membrane system. Control the operating pressure at 0.25 MPa and the temperature at 32 °C. Collect 7.5 L of permeate. The (R)-3-aminobutanol rejection rate is 1.5%.

[0049] S2. First, prepare a chiral molecularly imprinted adsorbent. The adsorbent is prepared by mixing the template molecule (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate in a molar ratio of 1:4:16. Add 1.2% (by mass) of azobisisobutyronitrile (AIBN) to the mixture. Polymerize at 62℃ for 13 h, pulverize through a 220-mesh sieve, and perform Soxhlet extraction with methanol-acetic acid (9:1) for 9 h. Dry under vacuum at 48℃ for 6.5 h. Adjust the pH of the permeate to 8.2 and pass it through a 1.8 L column containing the above adsorbent. Maintain a column temperature of 28℃ and a flow rate of 1.5 BV / h. Collect 7.3 L of effluent, and determine the ee value to be 99.5% and the (S)-isomer content to be 0.14%.

[0050] S3. The effluent was concentrated under reduced pressure at 50℃ and -0.08MPa to 1.6kg concentrate. 6.4kg of ternary composite solvent (isopropanol: methyl acetate: water = 8:1:1) was added, and the mixture was heated to 68℃ and stirred for 2h to dissolve. The temperature was then gradually decreased: the plastic was cooled to 30℃ at a rate of 5℃ / h, and then cooled to 5℃ at a rate of 2℃ / h and kept at that temperature for 4h to crystallize. After filtration, the product was dried under vacuum at 40℃ and -0.09MPa to obtain 0.37kg of product.

[0051] Product testing: Chemical purity 99.6%, ee value 99.8%, (S)-3-isomer 0.15%, total impurities 0.4%, no residual solvent, recovery rate 92.5%.

[0052] Example 3: This example provides a purification method for crude products with low ee values, as detailed below:

[0053] S1. Take 10L of crude (R)-3-aminobutanol reaction solution with an initial ee value of 85% (biocatalytic source, mass fraction 40%), pass it into an 80nm pore size polyethersulfone ultrafiltration membrane system, control the operating pressure at 0.18MPa and the temperature at 28℃, and collect 9.3L of permeate.

[0054] S2. First, prepare a chiral molecularly imprinted adsorbent. The adsorbent is prepared by mixing the template molecule (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate in a molar ratio of 1:6:19. Add 1.8% (by mass) of azobisisobutyronitrile (AIBN) of the total mass of the template molecule (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate. Polymerize at 68℃ for 15 h, pulverize through a 280-mesh sieve, and perform Soxhlet extraction with methanol-acetic acid (9:1) for 11 h. Dry under vacuum at 52℃ for 7.5 h. Adjust the pH of the permeate to 8.1 and pass it through a chromatography column containing the above adsorbent. The column temperature is 26℃, the flow rate is 2.5 BV / h, the ee value of the effluent is 99.5%, and the (S)-3-isomer content is 0.13%.

[0055] S3. The effluent was concentrated under reduced pressure at 50℃ and -0.08MPa to 1.4kg concentrate. 4.2kg of ternary composite solvent (isopropanol: methyl acetate: water = 7:2:1) was added, and the mixture was heated to 62℃ and stirred for 1.8h to dissolve. The mixture was then cooled in a gradient: at a rate of 5℃ / h to 30℃, and then at a rate of 2℃ / h to 2℃ for crystallization for 5h. After filtration, the mixture was dried under vacuum at 40℃ and -0.09MPa to obtain 0.36kg of product.

[0056] Product testing: purity 99.5%, ee value 99.8%, recovery rate 90.2% (the recovery rate is slightly lower due to the low initial ee value, but is still ≥90%).

[0057] Example 4: This example is an experiment on the recycling of a ternary composite solvent, as detailed below:

[0058] Solvent recycling: The 3.8 kg of ternary composite solvent recovered in Example 1 (referred to as "recycled once") was used for the purification of a new batch of crude product (same as the steps in Example 1), and the recycling was repeated 3 times;

[0059] One cycle: Product purity 99.6%, ee value 99.8%, recovery rate 91.8%;

[0060] After two cycles: product purity 99.5%, ee value 99.7%, recovery rate 91.2%;

[0061] After 3 cycles: product purity 99.5%, ee value 99.7%, recovery rate 90.5%;

[0062] The solvent does not affect product quality within 3 cycles, and the recovery rate is stable at ≥90%.

[0063] Example 5: This example provides a method for purifying a highly impure crude product, as detailed below:

[0064] S1. Take 8L of crude chemical synthesis reaction solution with a total impurity of 1.8% (mass fraction 42%, ee value 89%, containing unreacted raw materials and borate), pass it into a 120nm pore size polyethersulfone ultrafiltration membrane system, control the operating pressure at 0.22MPa and the temperature at 30℃, and collect 7.4L of permeate.

[0065] S2. First, prepare a chiral molecularly imprinted adsorbent. The adsorbent is prepared by mixing template molecules (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate in a molar ratio of 1:5:17. Add 1.4% (by mass) of azobisisobutyronitrile (AIBN) of the total mass of template molecules (R)-3-aminobutanol, methacrylic acid, and ethylene glycol dimethacrylate. Polymerize at 64℃ for 14 h, pulverize through a 240-mesh sieve, and perform Soxhlet extraction with methanol-acetic acid (9:1) for 9.5 h. Then, vacuum dry at 49℃ for 6.8 h. Adjust the pH of the permeate to 8.0 and pass it through a chromatography column containing the above adsorbent at 25℃. The total impurities in the effluent decrease to 0.6%, and the ee value is 99.6%.

[0066] S3. The effluent was concentrated under reduced pressure at 50℃ and -0.08MPa to 1.25kg concentrate. 5.0kg of ternary composite solvent (isopropanol: methyl acetate: water = 6:3:1) was added, and the mixture was heated to 65℃ and stirred for 2h to dissolve. The temperature was then gradually decreased: the plastic was cooled to 30℃ at a rate of 5℃ / h, and then cooled to 4℃ at a rate of 2℃ / h and kept at that temperature for 6h to crystallize. After filtration, the product was dried under vacuum at 40℃ and -0.09MPa to obtain 0.33kg of product.

[0067] Product testing results: purity 99.5%, total impurities 0.5%, ee value 99.8%, recovery rate 91.7%.

[0068] Example 6: To verify the superiority of the functional monomers and crosslinking agents selected in this invention, the following adsorbent comparison experiment was conducted: Acrylic acid and acrylamide were used instead of methacrylic acid as functional monomers, and divinylbenzene and trimethylolpropane triacrylate were used instead of ethylene glycol dimethacrylate as crosslinking agents. Different adsorbents were prepared according to the preparation method of the chiral molecularly imprinted adsorbent in Example 1 (only the corresponding monomers or crosslinking agents were replaced). Adsorption performance was tested under the same adsorption conditions (pH=8.0, column temperature 25℃, flow rate 2 BV / h), and the results are shown in Table 1 below:

[0069] Table 1

[0070] Functional unit Crosslinking agent Adsorption selectivity coefficient Effluent (S) - Isomer Content Methacrylic acid (Example 1) Ethylene glycol dimethacrylate (Example 1) ≥50 ≤0.15% acrylic acid Ethylene glycol dimethacrylate 22-28 0.35%-0.42% Acrylamide Ethylene glycol dimethacrylate 18-24 0.40%-0.48% methacrylic acid Divinylbenzene 25-30 0.32%-0.38% methacrylic acid Trimethylolpropane triacrylate 20-26 0.38%-0.45%

[0071] As can be seen from the comparative data above, the combination of methacrylic acid and ethylene glycol dimethacrylate selected in this embodiment of the invention produces an adsorbent with a significantly higher adsorption selectivity coefficient than other combinations, and a substantial reduction in the (S)-isomer content in the effluent, demonstrating unexpectedly excellent adsorption performance. This advantage stems from the stable hydrogen bonding and ionic interactions that can be formed between methacrylic acid and the template molecule (R)-3-aminobutanol, while ethylene glycol dimethacrylate has a suitable degree of cross-linking, enabling the construction of specific recognition sites that highly match the spatial structure of the template molecule. The synergistic effect of the two achieves highly efficient and selective adsorption of the (S)-3-aminobutanol isomer.

[0072] In summary, the stability of the process has been fully verified through multiple embodiments of this invention: it is not only adaptable to crude products from both biocatalysis and chemical synthesis sources, but also capable of processing raw materials with low ee values ​​and high impurity content, and the solvent can be recycled. All products obtained in all embodiments meet key indicators (purity ≥99.5%, ee ≥99.8%, isomers ≤0.15%, total impurities ≤1.0%, no residual solvent), with a yield ≥90%. Specifically, the chiral molecularly imprinted adsorbent, through a specific molar ratio of template molecules, functional monomers of methacrylic acid, and ethylene glycol dimethacrylate crosslinking agents, combined with optimized preparation process parameters, achieves adsorption performance far exceeding other monomer and crosslinking agent combinations. Comparative experiments have confirmed its unexpected advantages in selectivity and impurity removal. Compared with existing technologies, the method provided by the embodiments of this invention does not require the use of hazardous solvents, the steps are simplified, and it is easy to achieve large-scale production, effectively increasing the production capacity of (R)-3-aminobutanol, providing strong support for the industrialization of anti-AIDS drugs and anti-tumor drugs, and possessing significant economic and social benefits.

[0073] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification.

Claims

1. An integrated purification method for high-purity (R)-3-aminobutanol, characterized in that, Includes the following steps: Membrane separation pretreatment: The crude reaction solution containing (R)-3-aminobutanol is subjected to membrane separation to remove macromolecular impurities and the permeate is collected; Chiral molecular imprinted adsorption: Adjust the pH of the permeate and pass it through an adsorption unit filled with chiral molecular imprinted adsorbent to selectively adsorb (S)-3-aminobutanol isomers and polar impurities, and collect the effluent after adsorption. Ternary composite solvent recrystallization: The effluent is concentrated to obtain a concentrate; a ternary composite solvent is added to the concentrate for recrystallization, followed by solid-liquid separation and drying to obtain (R)-3-aminobutanol product; the ternary composite solvent includes isopropanol, methyl acetate and water.

2. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1, characterized in that, The membrane separation uses an ultrafiltration membrane for classification; the material of the ultrafiltration membrane is selected from one or more of polyethersulfone, polysulfone, and polyvinylidene fluoride, and its pore size is 50-200 nm.

3. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1 or 2, characterized in that, The membrane separation operates at a pressure of 0.1-0.3 MPa and a temperature of 25-35°C, with a target product rejection rate of ≤2%.

4. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1, characterized in that, The chiral molecularly imprinted adsorbent was prepared by bulk polymerization using (R)-3-aminobutanol as a template molecule, methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a crosslinking agent.

5. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 4, characterized in that, The preparation method of the chiral molecularly imprinted adsorbent includes the following steps: The template molecule, functional monomer, and crosslinking agent are mixed in a molar ratio of 1:(4-6):(15-20), an initiator is added, and a polymerization reaction is carried out at 60-70℃. The resulting polymer product is pulverized, sieved, extracted, and dried to obtain a chiral molecularly imprinted adsorbent.

6. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 5, characterized in that, The initiator is azobisisobutyronitrile, and its amount is 1%-2% of the total mass of the template molecule, functional monomer and crosslinking agent; the extraction is carried out by Soxhlet extraction with a mixture of methanol and acetic acid, and the volume ratio of methanol to acetic acid is (8.5-9.5):(0.5-1.5).

7. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1, characterized in that, The adsorption unit is a chromatography column; the operating conditions for the chiral molecular imprint adsorption are: adjusting the pH of the permeate to 7.5-8.5, the adsorption temperature to 20-30℃, and the flow rate to 1-3 BV / h.

8. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1, characterized in that, In the ternary composite solvent, the volume ratio of isopropanol, methyl acetate and water is (6-8):(3-1):

1.

9. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1, characterized in that, The mass ratio of the ternary composite solvent to the concentrate is (3-5):1; the recrystallization adopts a gradient cooling crystallization method, specifically as follows: after holding at 60-70℃ for 1-2 hours, the temperature is lowered to 20-40℃ at a rate of 4-6℃ / h, and then lowered to 0-5℃ at a rate of 1-3℃ / h, and crystallized at this temperature for 4-6 hours; the mother liquor obtained from crystallization is subjected to vacuum distillation to recover the ternary composite solvent, and the recovered ternary composite solvent is recycled for the recrystallization step.

10. The integrated purification method for high-purity (R)-3-aminobutanol according to claim 1, characterized in that, The crude product reaction solution is derived from a bio-enzyme catalytic process or a chemical synthesis process; the chemical synthesis process is the reduction of (R)-3-aminobutyric acid in an organic solvent by acid and borohydride; the (R)-3-aminobutanol in the crude product reaction solution has a mass fraction of 30%-60% and an optical purity ee value of 85%-95%; the (R)-3-aminobutanol product has a chemical purity ≥99.5%, an optical purity ee value ≥99.8%, and a total impurity content ≤1.0%.

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