Multi-column combined low and high pressure column chromatography device and process for purifying (s)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone reaction liquid

Abstract

The present application relates to a multi-column combined low-pressure column chromatography device and a process for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone reaction liquid. It comprises a sample column (1), a rough separation column (2), a fine separation column (3), a target product collection tank (4), a waste mobile phase collection tank (5), a waste mobile phase regeneration system (6), a mobile phase storage tank (7), a cleaning liquid storage tank (8), a waste liquid tank (9), a pump (10), and a valve (11). The device cooperates with a specific process to significantly improve the column chromatography separation efficiency and impurity removal capacity, completely separates the impurities with similar polarity, realizes high productivity and high impurity removal capacity under the condition of severe load overload of the chromatographic column, and correspondingly reduces the use amount of the mobile phase by more than 60%. The purity of the crude product after the column can reach more than 99%, and the yield is stable at more than 85%.

Description

Technical Field

[0001] This invention relates to the field of purification technology, specifically to a multi-column combined medium-low pressure column chromatography apparatus and a process for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution. Background Technology

[0002] (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone is the levorotatory optical isomer of piracetam. Compared to the dextrorotatory isomer, it has stronger efficacy, higher biological activity, and better potential therapeutic effects, and has important applications in the treatment of brain injury and related neurological deficits, memory and consciousness disorders. Currently, the preparation of this compound mainly uses ethyl S-4-chloro-3-hydroxybutyrate and glycine hydrochloride as raw materials, which are then purified after a chemical reaction to generate a reaction solution. Among the existing purification methods, ion exchange resin method, recrystallization method, and atmospheric pressure single column chromatography are difficult to effectively remove impurities with similar polarity, such as structural analogs, resulting in low product purity, high post-processing pressure, and serious defects that affect product quality and yield. In addition, in conventional chromatographic purification, when the chromatographic column is severely overloaded, the separation efficiency drops sharply, making it difficult to achieve both high production capacity and high purity. Therefore, developing a purification method that can efficiently remove impurities of similar polarity under severe overload conditions, is simple to operate, low in cost, environmentally friendly, and suitable for industrial production has become an urgent technical problem to be solved in this field.

[0003] Chinese invention patent application CN105820101A discloses a method for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone by single-column chromatography. However, the method is cumbersome, time-consuming, and requires a large amount of organic solvent, resulting in high production costs and making it unsuitable for large-scale production. Summary of the Invention

[0004] The first aspect of this invention provides a multi-column combined medium-low pressure column chromatography apparatus. The basic apparatus of the single-pump triple-column system includes: a sample loading column, a coarse separation column, a fine separation column, a target analyte collection tank, a waste mobile phase collection tank, a waste mobile phase regeneration system, a mobile phase storage tank, a washing solution storage tank, a waste liquid tank, a pump, and valves. The sample loading column, coarse separation column, and fine separation column are connected in series and parallel in sequence. The washing solution storage tank is connected to the pump, and the pump is connected to the inlet ends of the sample loading column, coarse separation column, and fine separation column via a four-way valve and a two-way valve, respectively. The outlet end of the fine separation column is connected to the waste mobile phase collection tank, the waste liquid tank, and the target analyte collection tank, respectively. The outlet end of the sample loading column is connected to the inlet end of the coarse separation column and the waste liquid tank of the waste mobile phase collection tank, respectively. The outlet end of the coarse separation column is connected to the inlet end of the fine separation column and the waste liquid tank of the waste mobile phase collection tank, respectively. The waste mobile phase collection tank, the waste mobile phase regeneration system, and the mobile phase storage tank are connected in sequence.

[0005] The multi-column combined medium-low pressure column chromatography device also includes a two-way valve, a three-way valve, or a four-way valve for controlling the flow direction of liquid in the pipeline.

[0006] The sample loading column is equipped with a three-way valve at its outlet end to control the connection with the waste mobile phase collection tank and the coarse separation column; the coarse separation column is equipped with a three-way valve at its inlet end to control the connection with the sample loading column and the mobile phase storage tank; the coarse separation column is equipped with a three-way valve at its outlet end to control the connection with the fine separation column and the waste mobile phase collection tank; the fine separation column is equipped with a three-way valve at its inlet end to control the connection with the mobile phase storage tank and the coarse separation column; and the fine separation column is equipped with a three-way valve at its outlet end to control the connection with the waste mobile phase collection tank and the target material collection tank.

[0007] The pump is selected from diaphragm pumps or plunger pumps and is used for transporting the mobile phase.

[0008] The number of loading columns, coarse fractionation columns, and fine fractionation columns are all 1-5.

[0009] Optionally, the number of sample loading columns, coarse dividing columns, and fine dividing columns is 1-3 each.

[0010] Optionally, when the number of the loading column, coarse fractionation column, and fine fractionation column is one, it is a single-pump triple column system, as shown in the example below. Figure 1 The diagram shows the basic connection device of the present invention.

[0011] Optionally, when the total number of the loading column, coarse column, and fine column is 4, it is a single-pump quadruple column; when the total number is 5, it is a single-pump quintuple column.

[0012] Optionally, the single-pump quadruple column configuration includes the following scenarios: 1 sample loading column, 1 coarse separation column, and 2 fine separation columns; 1 sample loading column, 2 coarse separation columns, and 1 fine separation column; or 2 sample loading columns, 1 coarse separation column, and 1 fine separation column.

[0013] Optionally, the single-pump five-column configuration includes the following configurations: 1 sample loading column, 2 coarse separation columns, and 2 fine separation columns; 2 sample loading columns, 2 coarse separation columns, and 1 fine separation column; 2 sample loading columns, 1 coarse separation column, and 2 fine separation columns; 3 sample loading columns, 1 coarse separation column, and 1 fine separation column; 1 sample loading column, 3 coarse separation columns, and 1 fine separation column; 1 sample loading column, 1 coarse separation column, and 3 fine separation columns.

[0014] Optionally, the sample loading columns are connected in series or in parallel, the coarse-grained columns are connected in series or in parallel, and the fine-grained columns are connected in series or in parallel.

[0015] The loading column, coarse separation column, and fine separation column are all filled with packing material.

[0016] The packing material in the loading column has a mesh size of 100-400 mesh, the packing material in the coarse separation column has a mesh size of 100-400 mesh, and the packing material in the fine separation column has a mesh size of 300-1000 mesh.

[0017] Optionally, the packing material in the sample loading column has a mesh size of 200-300 mesh, the packing material in the coarse separation column has a mesh size of 100-400 mesh, and the packing material in the fine separation column has a mesh size of 400-800 mesh.

[0018] The chromatography system used is either normal phase or reversed phase, and the packing material includes silica gel, amino-bonded silica gel, cyano-bonded silica gel, amide-bonded silica gel, alumina, and C. 18 At least one of bonded silica gel (ODS), C8 bonded silica gel, C4 bonded silica gel, and aromatic bonded silica gel, preferably silica gel.

[0019] Typically, the ratio of silica gel packing material to the material in purification chromatography is 30:1. Under severe column overload conditions, the adsorption sites are occupied by a large number of impurities, resulting in a significant decrease in column efficiency and making it difficult to effectively remove impurities and obtain high-purity products. In practical applications, the solution is to continuously increase the amount of packing material to 40:1 or even 50:1, which leads to unbearable quality, cost, environmental, and safety issues. This study found that by setting up a multi-column and multi-packing material combination of a loading column, a coarse separation column, a fine separation column, and multiple columns, a large amount of impurities are eluted from the front column before entering the rear column. By visually inspecting and using light to control the timing of entry into the rear column, the target solution entering the rear column will gradually become pure, the impurity effect will be greatly reduced, and the column efficiency of the rear column will be significantly improved. This enables the purification of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone under high overload conditions, while significantly reducing the amount of packing material used, significantly improving the column chromatography purification efficiency and impurity removal capacity, shortening the production time, and completely separating impurities with similar polarities. This achieves high production capacity and high impurity removal capacity under severe column overload conditions.

[0020] A second aspect of the present invention provides a process for purifying a (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution, the process employing the above-described apparatus and comprising the following steps:

[0021] S1, add the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone to the loading column, add the mobile phase in the mobile phase storage tank to the loading column for elution by pump, control the three-way valve at the outlet of the loading column to allow the waste mobile phase generated by the first elution to enter the waste mobile phase collection tank, and then control the three-way valve to connect the loading column and the coarse separation column.

[0022] S2, control the three-way valve at the outlet of the coarse column to allow the waste mobile phase generated by the first elution to enter the waste mobile phase collection tank, and then control the three-way valve to connect the fine column and the coarse column.

[0023] S3, control the three-way valve at the outlet of the fine separation column (3) to allow the waste mobile phase generated by the first elution to enter the waste mobile phase collection tank (5). When appropriate, control the three-way valve to connect the fine separation column (3) and the target material collection tank (4). When appropriate, stop the operation of the loading column (1) and the coarse separation column (2) in sequence and open the column top valve (11) of the coarse separation column (2) and the fine separation column (3) at the same time to keep the mobile phase flowing. The mobile phase in the waste mobile phase collection tank (5) is sent to the waste mobile phase regeneration system (6) for purification treatment and recycling. After the target material is collected, control the three-way valve to connect the cleaning liquid storage tank (8) to the loading column (1), the coarse separation column (2) and the fine separation column (3) in parallel to clean the packing in the loading column (1), the coarse separation column (2) and the fine separation column (3). The waste liquid obtained from the cleaning is sent to the waste liquid tank (9). The waste cleaning liquid is concentrated and disposed of as chemical waste.

[0024] S4. Concentrate the target product collected in the target product collection tank to obtain (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone.

[0025] The reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone includes the reddish-brown oily substance prepared in Example 1 of Chinese Invention Patent Application CN105820101A.

[0026] The mobile phase is a mixed solution comprising solvent A and solvent B. Solvent A is selected from one of dichloromethane, n-hexane, cyclohexane, petroleum ether, benzene, ethyl acetate, water, methanol, acetone, ethyl cyanide, isopropanol, and ethanol. Solvent B is selected from one of dichloromethane, n-hexane, cyclohexane, petroleum ether, benzene, ethyl acetate, water, methanol, acetone, ethyl cyanide, isopropanol, and ethanol. Preferably, the mixed solution is a mixture of dichloromethane and methanol.

[0027] The volume ratio of dichloromethane to methanol is (1-10):1.

[0028] Optionally, the volume ratio of dichloromethane to methanol is (4-10):1.

[0029] The total amount of packing material in the loading column, coarse column, and fine column is less than 20% of the weight of the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone.

[0030] Optionally, the total amount of packing material in the loading column, coarse column, and fine column is less than 15% of the weight of the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone.

[0031] The pressure in the loading column, coarse column, and fine column is 0.1-0.7 MPa.

[0032] Optionally, the pressure in the loading column, coarse column, and fine column is 0.2-0.6 MPa.

[0033] Beneficial effects

[0034] 1. By setting up loading columns, coarse separation columns, and fine separation columns, efficient purification of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone can be achieved under high overload conditions, while reducing the amount of packing material used and shortening the production time.

[0035] 2. The packing material in the loading column has a mesh size of 100-400 mesh, the packing material in the coarse separation column has a mesh size of 100-400 mesh, and the packing material in the fine separation column has a mesh size of 300-1000 mesh, which can reduce the amount of organic solvent used and improve the purification efficiency.

[0036] 3. By setting up target material collection tanks, waste mobile phase collection tanks, waste mobile phase regeneration systems, and mobile phase storage tanks, online recycling and reuse of waste mobile phases and online cleaning of waste packing can be achieved. The emissions are low, which is in line with the concept of green technology and has the potential to be transformed into an unmanned production line.

[0037] 4. The device of the present invention can be flexibly equipped with multiple subdivision columns or coarse division columns in series according to actual production needs, so as to further improve production capacity.

[0038] 5. The apparatus and process of the present invention can further improve the yield and purity of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone, resulting in a yield >85% and a purity >99%.

[0039] 6. The device of the present invention can be designed with high overload and high efficiency to separate and purify difficult-to-remove impurities under the principles of normal phase chromatography and reversed phase chromatography, so as to obtain a large quantity of high-purity industrial-grade products. Attached Figure Description

[0040] Figure 1 This is a schematic diagram of the multi-column combined medium-low pressure column chromatography apparatus in Example 1.

[0041] Figure 2 This is the liquid chromatogram of the product from Example 1.

[0042] Figure 3 This is the liquid chromatogram of the product from Example 2.

[0043] Figure 4 This is the liquid chromatogram of the product from Example 3.

[0044] Figure 5 This is the liquid chromatogram of the product from Example 4.

[0045] Figure 6 This is the liquid chromatogram of the product from Example 5.

[0046] The components include: 1. Sample loading column; 2. Coarse separation column; 3. Fine separation column; 4. Target analyte collection tank; 5. Waste mobile phase collection tank; 6. Waste mobile phase regeneration system; 7. Mobile phase storage tank; 8. Cleaning fluid storage tank; 9. Waste liquid tank; 10. Pump; 11. Valve. Detailed Implementation

[0047] Example 1

[0048] like Figure 1 As shown, a single-pump triple-column purification method was used: three transparent medium-pressure chromatography columns (two with an inner diameter of 20cm × height of 70cm and one with an inner diameter of 20cm × height of 50cm) were connected in series and parallel. The three 20cm × height columns were designated as sample loading column 1 and fine separation column 3, while the 20cm × height column was designated as coarse separation column 2. Sample loading column 1 and coarse separation column 2 were packed with 200-300 mesh coarse-pore silica gel, while fine separation column 3 was packed with 600-800 mesh fine-pore silica gel. The packing amounts were 15.5kg for sample loading column, 25.0kg for coarse separation column, and 13.6kg for fine separation column 3. 2.33kg of the reaction solution (a reddish-brown oily substance prepared according to Example 1 of Chinese Invention Patent Application CN105820101A) was added to an appropriate amount of 200-300 mesh coarse-pore silica gel and stirred into a paste. The paste was then added to sample loading column 1. Clean the equipment with methanol, install the column heads, turn on the mobile phase (dichloromethane:methanol approximately 8:1, V:V), open the waste liquid valve to release the waste liquid. After approximately 0.5 column volumes, switch the bottom three-way valve of sample column 1 to the coarse separation column, open the valve of coarse separation column 2 to collect the waste liquid. After approximately 3 column volumes, switch the bottom three-way valve of coarse separation column 2 to the fine separation column, open the bottom three-way valve of fine separation column 3 to collect the waste liquid. Continue running for 5 column volumes, then close the valve at the top of sample column 1 to stop the operation of sample column 1, and simultaneously open the valve at the top of coarse separation column 2. After running for approximately 8 column volumes, switch the bottom three-way valve of fine separation column 3 to the product collection line, and change the mobile phase (dichloromethane:methanol approximately 6:1, V:V). After approximately 25 column volumes, stop collecting, open all column head valves, connect the cleaning solution parallel line, start cleaning the packing material of each column, collect the waste liquid, and the purification process is complete. The mobile phase in the waste mobile phase collection tank 5 is recycled into the waste mobile phase regeneration system 6. The product-containing eluent is concentrated to near dryness, cooled to room temperature, added to the mobile phase solution for dispersion, filtered, and the filter cake is washed with the cold mobile phase solution to obtain 2.08 kg of white crystalline powder.

[0049] Example 2

[0050] Single-pump quadruple-column purification: Take four transparent medium-pressure chromatography columns (three with an inner diameter of 20cm and a height of 70cm; one with an inner diameter of 20cm and a height of 50cm) and connect them in series and parallel. The three columns with an inner diameter of 20cm and a height of 70cm are used as the sample loading column, the first sub-sub-column, and the second sub-sub-column, while the column with an inner diameter of 20cm and a height of 50cm is used as the coarse sub-column. The loading column and coarse separation column are packed with 200-300 mesh coarse-pore silica gel, the second fine separation column is packed with 300-500 mesh coarse-pore silica gel, and the first fine separation column is packed with 300-500 mesh fine-pore silica gel. The loading amounts are 4.5 kg for the loading column, 5 kg for the coarse separation column, 13.6 kg for the first fine separation column, and 5 kg for the second fine separation column. Take 2.58 kg of the reaction solution (refer to Chinese invention patent application CN105820101A, the reddish-brown oily substance prepared in Example 1), add an appropriate amount of 200-300 mesh coarse-pore silica gel and stir to form a paste. Add the paste to the loading column, clean the equipment with an appropriate amount of methanol, install the column head, turn on the mobile phase (dichloromethane:methanol approximately 8:1, V:V), open the waste liquid valve to release the waste liquid. After about 0.5 column volumes, switch the bottom three-way valve of the loading column to the coarse separation column, open the coarse separation column valve to collect the waste liquid. After about 3 column volumes... After approximately 10 column volumes, connect the bottom three-way valve of the coarse separation column to the first fine separation column, open the bottom three-way valve of the first fine separation column to collect waste liquid. After approximately 10 column volumes, close the column head valve of the loading column and stop the loading column operation. At the same time, open the column head valve of the coarse separation column and connect the bottom three-way valve of the first fine separation column to the second fine separation column. Open the bottom three-way valve of the second fine separation column to collect waste liquid. After approximately 2 column volumes, change the mobile phase (dichloromethane:methanol approximately 6:1, V:V) and continue running for approximately 8 column volumes. After approximately 5 column volumes, close the column head valve of the coarse separation column and stop the coarse separation column operation. At the same time, open the column head valve of the first fine separation column to check the product status of the second fine separation column. Connect the bottom three-way valve of the second fine separation column to the product collection line. After approximately 20 column volumes, stop collecting, open all column head valves, connect the parallel cleaning solution line, start cleaning the packing material of each column, collect waste liquid, and the purification process is complete. The product-containing eluent was concentrated to near dryness, cooled to room temperature, and dispersed in a mobile phase solution. After filtration, the filter cake was washed with a cold mobile phase solution to obtain 1.89 kg of white crystalline powder.

[0051] Example 3

[0052] Single-pump five-column purification: Take five transparent medium-pressure chromatography columns (three with an inner diameter of 20cm and a height of 70cm; two with an inner diameter of 20cm and a height of 50cm) and connect them in series and parallel. The three columns with an inner diameter of 20cm and a height of 70cm are divided into a sample loading column, a first fine fractionation column, and a second fine fractionation column. The columns with an inner diameter of 20cm and a height of 50cm are the first coarse fractionation column and the second coarse fractionation column. The loading column, the first coarse column, and the second coarse column are packed with 200-300 mesh coarse-pore silica gel. The second fine column is packed with 300-500 mesh coarse-pore silica gel, and the first fine column is packed with 300-500 mesh fine-pore silica gel. The total loading volume is 4.5 kg for the loading column, 5 kg each for the first and second coarse columns, 13.6 kg for the first fine column, and 5 kg for the second fine column. Take 2.82 kg of the reaction solution (a reddish-brown oily substance prepared according to Example 1 of Chinese Invention Patent Application CN105820101A), add an appropriate amount of 200-300 mesh coarse-pore silica gel, and stir to form a paste. Add the paste to the loading column, clean the equipment with an appropriate amount of methanol, install the column head, turn on the mobile phase (dichloromethane:methanol approximately 8:1, V:V), open the waste liquid valve to release the waste liquid, and after approximately 0.5 column volumes... Simultaneously connect the bottom three-way valve of the loading column to both the first and second coarse fractionating columns. Open the valves of both columns to collect waste liquid. After approximately 3 column volumes, connect the bottom three-way valves of both columns to the first fine fractionating column. Open the bottom three-way valve of the first fine fractionating column to collect waste liquid. After approximately 10 column volumes, connect the bottom three-way valve of the first fine fractionating column to the second fine fractionating column. Open the bottom three-way valve of the second fine fractionating column to collect waste liquid. Close the valve at the top of the loading column to stop the loading column operation. Simultaneously open the valve at the top of the first coarse fractionating column. After approximately 2 column volumes, replace the mobile phase (dichloromethane:methanol approximately 6:1, V:V). Continue operation for approximately 8 column volumes. After approximately 5 column volumes, simultaneously close the valves at the top of both columns to stop the operation of both columns. Simultaneously open the valve at the top of the first fine fractionating column. To examine the product status of the second fractionation column, the three-way valve at the bottom of the second fractionation column was switched into the product collection line. Collection was stopped after approximately 20 column volumes. All column head valves were opened, the parallel cleaning solution line was connected, and the cleaning of the column packing was initiated. The waste liquid was collected, completing the purification process. The product-containing eluent was concentrated to near dryness, cooled to room temperature, and dispersed in the mobile phase solution. The solution was filtered, and the filter cake was washed with the cold mobile phase solution, yielding 2.22 kg of a white crystalline powder.

[0053] Example 4

[0054] Single-pump five-column purification: Take five transparent medium-pressure chromatography columns (four with an inner diameter of 20cm and a height of 70cm; one with an inner diameter of 20cm and a height of 50cm) and connect them in series and parallel. The four columns with an inner diameter of 20cm and a height of 70cm are divided into the first sample loading column, the second sample loading column, the first subdivision column, and the second subdivision column. The column with an inner diameter of 20cm and a height of 50cm is the coarse subdivision column. The first and second loading columns, and the coarse-filtration column are filled with 200-300 mesh coarse-pore silica gel; the second fine-filtration column is filled with 300-500 mesh coarse-pore silica gel; and the first fine-filtration column is filled with 300-500 mesh fine-pore silica gel. The loading amounts are 4.5 kg each for the first and second loading columns, 5 kg for the coarse-filtration column, 13.6 kg for the first fine-filtration column, and 5 kg for the second fine-filtration column. 2.78 kg of the reaction solution (a reddish-brown oily substance prepared according to Example 1 of Chinese Invention Patent Application CN105820101A) is taken and injected into the first and second loading columns in equal volumes. The equipment is cleaned with an appropriate amount of methanol before installation. Turn on the mobile phase (dichloromethane:methanol approximately 8:1, V:V) and release the waste liquid through the waste valve. After approximately 0.5 column volumes, switch the bottom three-way valves of the first and second sample loading columns to the coarse separation column. Open the coarse separation column valve to collect the waste liquid. After approximately 3 column volumes, switch the bottom three-way valve of the coarse separation column to the first fine separation column and open the bottom three-way valve of the first fine separation column to collect the waste liquid. After approximately 10 column volumes, switch the bottom three-way valve of the first fine separation column to the second fine separation column and open the bottom three-way valve of the second fine separation column to collect the waste liquid. Close the valves at the top of the first and second sample loading columns to stop the operation of the first and second sample loading columns, and simultaneously open the valve at the top of the coarse separation column. After approximately 2 column volumes, change the mobile phase (dichloromethane:methanol approximately 6:1, V:V) and continue running for approximately 8 column volumes. After approximately 5 column volumes, close the valve at the top of the coarse separation column to stop the operation of the coarse separation column, and simultaneously open the valve at the top of the first fine separation column. To assess the product status of the second fractionation column, connect the three-way valve at the bottom of the column to the product collection line. After approximately 20 column volumes, stop collecting. Open all column head valves, connect the parallel cleaning solution line, and begin cleaning the packing material of each column. Collect the waste liquid; the purification process is complete. Concentrate the product-containing eluent to near dryness, cool to room temperature, and disperse in the mobile phase solution. Filter, and wash the filter cake with the cold mobile phase solution to obtain 2.16 kg of white crystalline powder, which is the final product.

[0055] Example 5

[0056] Single-pump five-column purification: Take five transparent medium-pressure chromatography columns (two with an inner diameter of 20cm and a height of 70cm; three with an inner diameter of 20cm and a height of 50cm) and connect them in series and parallel. The two columns with an inner diameter of 20cm and a height of 70cm are used as the sample loading column and the fine separation column, respectively. The columns with an inner diameter of 20cm and a height of 50cm are used as the first coarse separation column, the second coarse separation column, and the third coarse separation column. The loading column, the first coarse separation column, the second coarse separation column, and the third coarse separation column are each packed with 200-300 mesh coarse-pore silica gel, and the fine separation column is packed with 600-800 mesh fine-pore silica gel. The packing amounts are: 5.0 kg for the loading column, 5.0 kg for the first coarse separation column, 7.0 kg for the second and third coarse separation columns, and 15.0 kg for the fine separation column. Take 2.80 kg of the reaction solution (refer to Chinese invention patent application CN105820101A, the reddish-brown oily substance prepared in Example 1), add an appropriate amount of 200-300 mesh coarse-pore silica gel and stir to form a paste. Add the paste to the loading column, clean the equipment with an appropriate amount of methanol, install the column head, and turn on the mobile phase (II). The ratio of chloromethane to methanol is approximately 8:1 (V:V). Open the waste liquid valve to release the waste liquid. After approximately 0.5 column volumes, switch the bottom three-way valve of the loading column to the first coarse fractionation column. Open the valve of the first coarse fractionation column to collect the waste liquid. After approximately 3 column volumes, switch the bottom three-way valve of the first coarse fractionation column to the second coarse fractionation column. Open the bottom three-way valve of the second coarse fractionation column to collect the waste liquid. After approximately 5 column volumes, switch the bottom three-way valve of the second coarse fractionation column to the third coarse fractionation column. Open the bottom three-way valve of the third coarse fractionation column to collect the waste liquid. After approximately 5 column volumes, switch the bottom three-way valve of the third coarse fractionation column to the fine fractionation column. Open the bottom three-way valve of the fine fractionation column to collect the waste liquid. Close the valve at the top of the loading column to stop the loading column operation. Simultaneously, open the valve at the top of the first coarse fractionation column. The mobile phase ratio was changed to approximately 4:1 (V:V) of dichloromethane:methanol. After running for about 5 column volumes, the valves at the head of the first and second coarse fractionating columns were closed sequentially, stopping the operation of the first and second coarse fractionating columns. Simultaneously, the valve at the head of the third coarse fractionating column was opened. The product development of the fine fractionating columns was observed. Based on the development, the three-way valve at the bottom of the fine fractionating columns was switched to the product collection line. After about 20 column volumes, collection was stopped, all column head valves were opened, the parallel line for the cleaning solution was connected, and the cleaning of the packing material of each column was started. The waste liquid was collected, and the purification process was completed. The eluent containing the product was concentrated to near dryness, cooled to room temperature, and dispersed in the mobile phase solution. After filtration, the filter cake was washed with the cold mobile phase solution, yielding 2.37 kg of white crystalline powder, which is the product.

[0057] Performance testing methods

[0058] The purity of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone obtained in the examples was tested (HPLC, area normalization method). The liquid chromatograms of Examples 1-5 are shown below. Figure 2-6 As shown, the test data is listed in Table 1.

[0059] Performance test data

[0060] Table 1

[0061] Example Yield % purity% Example 1 89 99.87 Example 2 90 99.64 Example 3 85 99.48 Example 4 86 99.51 Example 5 85 99.35

Claims

1. A process for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution, characterized in that, The process employs a multi-column combined medium-low pressure column chromatography apparatus, which includes: a sample loading column (1), a coarse separation column (2), a fine separation column (3), a target analyte collection tank (4), a waste mobile phase collection tank (5), a waste mobile phase regeneration system (6), a mobile phase storage tank (7), a washing solution storage tank (8), a waste liquid tank (9), a pump (10), and a valve (11). The sample loading column (1), coarse separation column (2), and fine separation column (3) are connected in series and parallel. The washing solution storage tank (8) is connected to the pump (10), and the pump (10) is connected to the sample loading column (1), coarse separation column (2), and fine separation column (3) respectively through a four-way valve (11). The inlet end of the column (1) is connected to the coarse separation column (2), the waste mobile phase collection tank (5), the waste liquid tank (9), and the target material collection tank (4), respectively. The outlet end of the column (1) is connected to the inlet end of the coarse separation column (2), the waste mobile phase collection tank (5), and the waste liquid tank (9), respectively. The outlet end of the coarse separation column (2) is connected to the inlet end of the column (3), the waste mobile phase collection tank (5), and the waste liquid tank (9), respectively. The waste mobile phase collection tank (5), the waste mobile phase regeneration system (6), and the mobile phase storage tank (7) are connected in sequence. The column (1), the coarse separation column (2), and the column (3) are all filled with packing material. The process includes the following steps: S1, add the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone to the loading column (1), add the mobile phase in the mobile phase storage tank (7) to the loading column (1) via pump (10) for elution, control the three-way valve at the outlet end of the loading column (1) to allow the waste mobile phase generated by the first elution to enter the waste mobile phase collection tank (5), and then control the three-way valve to connect the loading column (1) and the coarse separation column (2); S2, control the three-way valve at the outlet of the coarse separator (2) to allow the waste mobile phase generated by the first washing to enter the waste mobile phase collection tank (5), and then control the three-way valve to connect the fine separator (3) and the coarse separator (2); S3, control the three-way valve at the outlet of the fine separation column (3) to allow the waste mobile phase generated by the first elution to enter the waste mobile phase collection tank (5), and control the three-way valve to connect the fine separation column (3) and the target collection tank (4) in a timely manner, and stop the operation of the loading column (1) and the coarse separation column (2) in a timely manner. When the loading column (1) is stopped, open the column top valve (11) of the coarse separation column (2). When the coarse separation column (2) is stopped, open the column top valve (11) of the fine separation column (3) to keep the mobile phase flowing. The mobile phase in the waste mobile phase collection tank (5) is sent to the waste mobile phase regeneration system (6) for purification and recycling. After the target is collected, control the three-way valve to connect the cleaning liquid storage tank (8) to the loading column (1), the coarse separation column (2) and the fine separation column (3) in parallel to clean the packing in the loading column (1), the coarse separation column (2) and the fine separation column (3). The waste liquid obtained from the cleaning is sent to the waste liquid tank (9). The waste cleaning liquid is concentrated and disposed of as chemical waste. S4, concentrate the target product collected in the target product collection tank (4) to obtain (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone.

2. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The multi-column combined medium-low pressure column chromatography device also includes a two-way valve, a three-way valve, or a four-way valve for controlling the flow direction of liquid in the pipeline.

3. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The number of each of the sample loading column (1), coarse separation column (2), and fine separation column (3) is 1-5.

4. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The number of each of the sample loading column (1), coarse sizing column (2), and fine sizing column (3) is 1-3.

5. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The chromatography system used is either normal phase or reversed phase, and the packing material includes amino-bonded silica gel, cyano-bonded silica gel, amide-bonded silica gel, alumina, and C. 18 The sample contains at least one of bonded silica gel, C8 bonded silica gel, C4 bonded silica gel, and aromatic bonded silica gel. The mesh size of the packing material in the loading column (1) is 100-400 mesh, the mesh size of the packing material in the coarse separation column (2) is 100-400 mesh, and the mesh size of the packing material in the fine separation column (3) is 300-1000 mesh.

6. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The mobile phase is a mixed solution comprising solvent A and solvent B. Solvent A is selected from one of dichloromethane, n-hexane, cyclohexane, petroleum ether, benzene, ethyl acetate, water, methanol, acetone, acetonitrile, isopropanol, and ethanol. Solvent B is selected from one of dichloromethane, n-hexane, cyclohexane, petroleum ether, benzene, ethyl acetate, water, methanol, acetone, acetonitrile, isopropanol, and ethanol.

7. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 6, characterized in that, The mixed solution is a mixture of dichloromethane and methanol.

8. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The total amount of packing material in the loading column (1), coarse column (2) and fine column (3) is less than 20% of the weight ratio of the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone.

9. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 1, characterized in that, The pressure in the loading column (1), coarse fractionation column (2) and fine fractionation column (3) is 0.1-0.7 MPa.

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