Multi-column combined medium and low pressure column chromatography device and process for purifying (S)-1-(carbamoyl) methyl-4-hydroxy-2-pyrrolidone reaction liquid

Abstract

The invention relates to a multi-column combined type medium and low pressure column chromatography device and a process for purifying (S)-1-(carbamoyl) methyl-4-hydroxy-2-pyrrolidone reaction liquid. Comprising a sample loading column (1), a coarse separation column (2), a fine separation column (3), a target object 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 disclosed by the invention is matched with a specific process to remarkably improve the column chromatography separation efficiency and the impurity removal capacity, impurities with similar polarity are completely separated, high productivity and high impurity removal capacity are kept under the working condition of serious overload of a chromatographic column, the use amount of a mobile phase is correspondingly reduced by more than 60%, the purity of a post-column crude product can reach more than 99%, and the method is suitable for industrial production. And the yield is stabilized at 85% or above.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of purification technology, in particular, to a multi-column combined medium-low pressure column chromatography device and a process for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone reaction solution. BACKGROUND

[0002] (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone is the left optical isomer of oxiracetam, which has stronger drug efficacy, higher biological activity and better potential therapeutic effect than the right optical isomer, and has important application in the treatment of brain injury and related neurological deficits, memory and consciousness disorders and the like. At present, the preparation of the compound is mostly based on S-4-chloro-3-hydroxybutyric acid ethyl ester and glycineamide hydrochloride as raw materials, and then purified after chemical reaction to generate a reaction solution. In the existing purification method, it is difficult to effectively remove impurities with similar structures and similar polarities by ion exchange resin method, recrystallization method and atmospheric pressure single column chromatography method, resulting in low product purity, large post-treatment pressure and other defects, which seriously affect the product quality and yield. In addition, in the conventional chromatographic purification, when the chromatographic column is seriously overloaded, the separation efficiency decreases sharply, and it is difficult to balance high productivity and high purity. Therefore, developing a purification method which can efficiently remove impurities with similar polarities under serious overload conditions, is simple to operate, low in cost, green and environmentally friendly, and suitable for industrial production, has become a technical problem to be solved in the field.

[0003] Chinese patent application CN105820101A discloses a method for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone by single column chromatography, but the operation is complicated, time-consuming, and a large amount of organic solvent is consumed, resulting in high production cost, and the method cannot meet the needs of large-scale production. SUMMARY

[0004] The first aspect of the present application provides a multi-column combined medium-low pressure column chromatography device, a single-pump triple-column system basic device comprising: a sample column, a rough separation column, a fine separation column, a target product collection tank, a waste mobile phase collection tank, a waste mobile phase regeneration system, a mobile phase storage tank, a cleaning liquid storage tank, a waste liquid tank, a pump, and a valve; the sample column, the rough separation column, and the fine separation column are connected in series and in parallel; the cleaning liquid storage tank is connected with the pump, and the pump is connected with the inlet end of the sample column, the rough separation column, and the fine separation column through a four-way valve and a two-way valve; the outlet end of the fine separation column is in communication with the waste mobile phase collection tank, the waste liquid tank, and the target product collection tank; the outlet end of the sample column is connected with the inlet end of the rough separation column, the waste mobile phase collection tank, and the waste liquid tank, and the outlet end of the rough separation column is connected with the inlet end of the fine separation column, the waste mobile phase collection tank, and the waste liquid tank; and 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 low-pressure column chromatography device further comprises a two-way valve, a three-way valve or a four-way valve for controlling the flow direction of the liquid in the pipeline.

[0006] The outlet end of the sample loading column is provided with a three-way valve for controlling the communication with the waste mobile phase collection tank and the coarse separation column; the inlet end of the coarse separation column is provided with a three-way valve for controlling the communication with the sample loading column and the mobile phase storage tank; the outlet end of the coarse separation column is provided with a three-way valve for controlling the communication with the fine separation column and the waste mobile phase collection tank; the inlet end of the fine separation column is provided with a three-way valve for controlling the communication with the mobile phase storage tank and the coarse separation column; and the outlet end of the fine separation column is provided with a three-way valve for controlling the communication with the waste mobile phase collection tank and the target product collection tank.

[0007] The pump is selected from a diaphragm pump or a plunger pump for conveying the mobile phase.

[0008] The number of the sample loading column, the coarse separation column and the fine separation column is 1-5.

[0009] Optionally, the number of the sample loading column, the coarse separation column and the fine separation column is 1-3.

[0010] Optionally, when the number of the sample loading column, the coarse separation column and the fine separation column is 1, it is a single-pump triple-column, and the single-pump triple-column is as shown in the following table. Figure 1 The basic connection device of the application is shown in the following table.

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

[0012] Optionally, the single-pump quadruple-column comprises the following cases: one sample loading column, one coarse separation column and two fine separation columns; one sample loading column, two coarse separation columns and one fine separation column; two sample loading columns, one coarse separation column and one fine separation column.

[0013] Optionally, the single-pump quintuple-column comprises the following cases: one sample loading column, two coarse separation columns and two fine separation columns; two sample loading columns, two coarse separation columns and one fine separation column; two sample loading columns, one coarse separation column and two fine separation columns; three sample loading columns, one coarse separation column and one fine separation column; one sample loading column, three coarse separation columns and one fine separation column; one sample loading column, one coarse separation column and three fine separation columns.

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

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

[0016] The mesh number of the filler in the sample loading column is 100-400 mesh, the mesh number of the filler in the coarse separation column is 100-400 mesh, and the mesh number of the filler in the fine separation column is 300-1000 mesh.

[0017] Optionally, the mesh number of the filler in the sample loading column is 200-300 mesh, the mesh number of the filler in the coarse separation column is 100-400 mesh, and the mesh number of the filler in the fine separation column is 400-800 mesh.

[0018] The filler includes at least one of silica gel, amino-bonded silica gel, cyano-bonded silica gel, amide-bonded silica gel, alumina, C 18 bonded silica gel (ODS), C8-bonded silica gel, C4-bonded silica gel, aryl-bonded silica gel, preferably silica gel.

[0019] Generally, the ratio of the filler to the material in the silica gel purification chromatography is 30:1. In the case of severe overloading of the chromatographic column, the adsorption sites are occupied by a large amount of impurities, the column efficiency is greatly reduced, and it is difficult to effectively remove the impurities and obtain high-purity products. In actual use, the solution is to continuously increase the amount of filler to 40:1 or even 50:1, thereby causing quality, cost, environmental protection, and safety problems. The present application finds that by setting a sample loading column, a coarse separation column, and a fine separation column in series, a large amount of eluted impurities are discarded in the front column and then enter the rear column. The target solution entering the rear column is gradually purified by visual observation and light control, the impurity effect is greatly reduced, the column efficiency of the rear column is significantly improved, and the purification of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone is completed under high overload. At the same time, the use amount of the filler is significantly reduced, the column chromatography purification efficiency and impurity removal capacity are significantly improved, the production time is shortened, the separation of impurities with similar polarity is complete, and high productivity and high impurity removal capacity are achieved under the condition of severe overloading of the chromatographic column.

[0020] The second aspect of the present application provides a process for purifying a (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone reaction solution, which uses the device described above and includes the following steps:

[0021] S1, the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone is added to the sample loading column, the mobile phase in the mobile phase storage tank is added to the sample loading column through the pump for elution, and the three-way valve at the outlet end of the sample loading column is controlled to make the waste mobile phase produced by the first elution enter the waste mobile phase collection tank, and then the three-way valve is controlled to connect the sample loading column and the coarse separation column;

[0022] S2, the three-way valve at the outlet end of the coarse separation column is controlled to make the waste mobile phase produced by the first elution enter the waste mobile phase collection tank, and then the three-way valve is controlled to connect the fine separation column and the coarse separation column;

[0023] S3, controlling the three-way valve at the outlet end of the fine column (3) to make the waste mobile phase generated by the first elution enter the waste mobile phase collection tank (5), and in time controlling the three-way valve to connect the fine column (3) and the target product collection tank (4), and in time sequentially stopping the operation of the sample column (1) and the coarse column (2) and simultaneously opening the column top valve (11) of the coarse column (2) and the fine column (3) to maintain the flow of the mobile phase. The mobile phase in the waste mobile phase collection tank (5) is introduced into the waste mobile phase regeneration system (6) for purification treatment and recycling. After the collection of the target product is completed, the three-way valve is controlled to connect the washing liquid storage tank (8) with the sample column (1), the coarse column (2) and the fine column (3) in parallel, and the fillers in the sample column (1), the coarse column (2) and the fine column (3) are washed. The waste liquid obtained by washing is introduced into the waste liquid tank (9), and the waste washing liquid is concentrated and disposed as chemical waste;

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

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

[0026] The mobile phase is a mixed solution, which includes A solvent and B solvent, the A solvent is selected from one of dichloromethane, n-hexane, cyclohexane, petroleum ether, benzene, ethyl acetate, water, methanol, acetone, ethyl cyanide, isopropyl alcohol, and ethanol; the B solvent is selected from one of dichloromethane, n-hexane, cyclohexane, petroleum ether, benzene, ethyl acetate, water, methanol, acetone, ethyl cyanide, isopropyl alcohol, and ethanol; preferably, the mixed solution is a dichloromethane and methanol mixed solution.

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

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

[0029] The weight ratio of the total amount of fillers in the sample column, the coarse column and the fine column to the reaction liquid containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone is <20.

[0030] Optionally, the weight ratio of the total amount of fillers in the sample column, the coarse column and the fine column to the reaction liquid containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone is <15.

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

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

[0033] Advantages

[0034] 1. By setting the loading column, the rough fractionation column and the fine fractionation column, high-efficiency purification of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone can be completed under high overload, while the use amount of filler is reduced and the production time is shortened.

[0035] 2. The mesh number of the filler in the loading column is 100-400 mesh, the mesh number of the filler in the rough fractionation column is 100-400 mesh, and the mesh number of the filler in the fine fractionation column is 300-1000 mesh, which can reduce the amount of organic solvent and improve the purification efficiency.

[0036] 3. By setting the target collection tank, the waste mobile phase collection tank, the waste mobile phase regeneration system and the mobile phase storage tank, online recycling and reuse of waste mobile phase and online cleaning of waste filler can be realized, the discharge amount is low, the green process concept is met, and the potential for transformation into an unmanned production line is possessed.

[0037] 4. The device can be flexibly installed and connected in series with multiple fine fractionation columns or rough fractionation columns according to actual production needs, further improving the production capacity.

[0038] 5. The device and the process thereof can further improve the yield and purity of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone, so that the yield is >85% and the purity is >99%.

[0039] 6. The device can be used under the principle system of normal phase chromatography and reverse phase chromatography to design a high-overload high-efficiency separation and purification process for difficult impurities, and a large amount of high-purity industrial-grade products can be obtained. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 It is a schematic diagram of the multi-column combined low-pressure column chromatography device of Example 1.

[0041] Figure 2 It is a product liquid chromatogram of Example 1.

[0042] Figure 3 It is a product liquid chromatogram of Example 2.

[0043] Figure 4 It is a product liquid chromatogram of Example 3.

[0044] Figure 5 It is a product liquid chromatogram of Example 4.

[0045] Figure 6 It is a product liquid chromatogram of 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 four column purification: four transparent medium pressure chromatographic columns (inner diameter 20 cm x height 70 cm three; inner diameter 20 cm x height 50 cm one) are connected in series and parallel, three inner diameter 20 cm x height 70 cm size columns are divided into sample column, first subdivision column, second subdivision column, and inner diameter 20 cm x height 50 cm size column is a coarse column. The sample column and the coarse column are packed with 200-300 mesh coarse pore silica gel, the second subdivision column is packed with 300-500 mesh coarse pore silica gel, and the first subdivision column is packed with 300-500 mesh fine pore silica gel. The packing amount is 4.5 kg for the sample column, 5 kg for the coarse column, 13.6 kg for the first subdivision column, and 5 kg for the second subdivision column. Take 2.58 kg of methanol solution of reaction liquid (red-brown oil prepared according to Chinese invention patent application CN105820101A, Example 1), stir with an appropriate amount of 200-300 mesh coarse pore silica gel to form a paste, and then pour the paste into the sample column. Wash the device with an appropriate amount of methanol, install the column head, open the mobile phase (dichloromethane:methanol about 8:1, V:V), open the waste valve to discharge the waste liquid, about 0.5 column volume, then cut the sample column bottom three-way valve into the coarse column, open the coarse column valve to collect the waste liquid, about 3 column volumes, then cut the coarse column bottom three-way valve into the first subdivision column, open the first subdivision column bottom three-way valve to collect the waste liquid, about 10 column volumes, then close the sample column head valve, stop the sample column running, at the same time open the coarse column head valve, cut the first subdivision column bottom three-way valve into the second subdivision column, open the second subdivision column bottom three-way valve to collect the waste liquid, about 2 column volumes, then change the mobile phase (dichloromethane:methanol about 6:1, V:V), continue to run for about 8 column volumes, about 5 column volumes, close the coarse column head valve, stop the coarse column running, at the same time open the first subdivision column head valve, check the product state of the second subdivision column, cut the second subdivision column bottom three-way valve into the product collection pipeline, stop collecting after about 20 column volumes, open all column head valves, connect the washing liquid parallel pipeline, open the washing column packing, collect the waste liquid, and the purification process is completed. Concentrate the product eluent containing to near dryness, cool to room temperature, disperse in the mobile phase solution, filter, wash the filter cake with cold mobile phase solution, and obtain 1.89 kg of white crystalline powder, which is obtained.

[0051] Example 3

[0052] Single pump five-column purification: five transparent medium-pressure chromatographic columns (three with an inner diameter of 20 cm and a height of 70 cm, and two with an inner diameter of 20 cm and a height of 50 cm) are connected in series and parallel. The three columns with an inner diameter of 20 cm and a height of 70 cm are divided into a sample column, a first sub-column, and a second sub-column. The two columns with an inner diameter of 20 cm and a height of 50 cm are used as a first coarse column and a second coarse column. The sample column, the first coarse column, and the second coarse column are packed with 200-300 mesh coarse-pore silica gel, the second sub-column is packed with 300-500 mesh coarse-pore silica gel, the first sub-column is packed with 300-500 mesh fine-pore silica gel, and the packing amount is 4.5 kg for the sample column, 5 kg for each of the first coarse column and the second coarse column, 13.6 kg for the first sub-column, and 5 kg for the second sub-column. 2.82 kg of a methanol solution of the reaction liquid (a red-brown oily substance prepared according to Example 1 of Chinese patent application CN105820101A) is stirred into a paste with an appropriate amount of 200-300 mesh coarse-pore silica gel, and the paste is fed into the sample column. The apparatus is washed with an appropriate amount of methanol, the column head is installed, the mobile phase (dichloromethane:methanol at about 8:1, V:V) is started, the waste liquid valve is opened to discharge the waste liquid, and after about 0.5 column volumes, the sample column bottom three-way valve is simultaneously switched into the first coarse column and the second coarse column, the first coarse column and the second coarse column valves are opened to collect the waste liquid, and after about 3 column volumes, the first coarse column and the second coarse column bottom three-way valves are switched into the first sub-column, the first sub-column bottom three-way valve is opened to collect the waste liquid, and after about 10 column volumes, the first sub-column bottom three-way valve is switched into the second sub-column, the second sub-column bottom three-way valve is opened to collect the waste liquid, the sample column head valve is closed, the sample column operation is stopped, the first coarse column head valve is opened, the mobile phase is changed (dichloromethane:methanol at about 6:1, V:V) after about 2 column volumes, the operation is continued for about 8 column volumes, the first coarse column and the second coarse column head valves are closed at about 5 column volumes, the operation of the first coarse column and the second coarse column is stopped, and the first sub-column head valve is opened. The product state of the second sub-column is observed, the second sub-column bottom three-way valve is switched into the product collection pipeline, the collection is stopped after about 20 column volumes, all the column head valves are opened, the washing liquid parallel pipeline is connected, the column packing is washed, the waste liquid is collected, and the purification process is completed. The product eluent containing the product is concentrated to near dryness, cooled to room temperature, dispersed in the mobile phase solution, filtered, and the filter cake is washed with cold mobile phase solution to obtain 2.22 kg of white crystalline powder, which is obtained.

[0053] Example 4

[0054] Single pump five-column purification: five transparent medium-pressure chromatographic columns (four of 20 cm inner diameter x 70 cm high; one of 20 cm inner diameter x 50 cm high) are connected in series and parallel, the four 20 cm inner diameter x 70 cm high columns are divided into a first sample column, a second sample column, a first subdivision column, and a second subdivision column, and the 20 cm inner diameter x 50 cm high column is a coarse column. The first sample column, the second sample column, and the coarse column are packed with 200-300 mesh coarse-pore silica gel, the second subdivision column is packed with 300-500 mesh coarse-pore silica gel, and the first subdivision column is packed with 300-500 mesh fine-pore silica gel. The packing amount is 4.5 kg for the first sample column and the second sample column, 5 kg for the coarse column, 13.6 kg for the first subdivision column, and 5 kg for the second subdivision column. Take 2.78 kg of the methanol solution of the reaction liquid (red-brown oily substance prepared according to Example 1 of Chinese Invention Patent Application CN105820101A), and inject the solution into the first sample column and the second sample column in equal amounts. Clean the instruments with an appropriate amount of methanol, install the column head, open the mobile phase (dichloromethane:methanol is about 8:1, V:V), open the waste valve to discharge the waste liquid, and after about 0.5 column volumes, cut the first sample column and the second sample column bottom three-way valve into the coarse column, open the coarse column valve to collect the waste liquid, and after about 3 column volumes, cut the coarse column bottom three-way valve into the first subdivision column, open the first subdivision column bottom three-way valve to collect the waste liquid, and after about 10 column volumes, cut the first subdivision column bottom three-way valve into the second subdivision column, open the second subdivision column bottom three-way valve to collect the waste liquid, close the first sample column and the second sample column head valve, stop the first sample column and the second sample column, and open the coarse column head valve. After about 2 column volumes, change the mobile phase (dichloromethane:methanol is about 6:1, V:V), continue to run for about 8 column volumes, close the coarse column head valve at about 5 column volumes, stop the coarse column, and open the first subdivision column head valve. Investigate the product state of the second subdivision column, cut the second subdivision column bottom three-way valve into the product collection pipeline, stop collecting after about 20 column volumes, open all the column head valves, connect the cleaning liquid parallel pipeline, open the cleaning column filler, collect the waste liquid, and complete the purification process. Concentrate the product eluent containing the product to near dryness, cool to room temperature, disperse in the mobile phase solution, filter, wash the filter cake with cold mobile phase solution, and obtain 2.16 kg of white crystalline powder, which is obtained.

[0055] Example 5

[0056] Single pump five-column purification: five transparent medium-pressure chromatographic columns (inner diameter 20 cm x height 70 cm two; inner diameter 20 cm x height 50 cm three) were connected in series and parallel, two inner diameter 20 cm x height 70 cm columns were divided into sample column and fine column, and the inner diameter 20 cm x height 50 cm columns were the first, second and third coarse column. The sample column, the first coarse column, the second coarse column and the third coarse column were packed with 200-300 mesh coarse pore silica gel, and the fine column was packed with 600-800 mesh fine pore silica gel. The packing amount was 5.0 kg for the sample column, 5.0 kg for the first coarse column, 7.0 kg for the second and third coarse columns, and 15.0 kg for the fine column. Take 2.80 kg of methanol solution of the reaction liquid (red-brown oily substance prepared according to Chinese invention patent application CN105820101A, Example 1), stir into paste with appropriate amount of 200-300 mesh coarse pore silica gel, and then pour the paste into the sample column. Wash the device with appropriate amount of methanol, install the column head, open the mobile phase (dichloromethane:methanol about 8:1, V:V), open the waste valve to discharge waste liquid, about 0.5 column volume, then cut the sample column bottom three-way valve into the first coarse column, open the first coarse column valve to collect waste liquid, about 3 column volumes, then cut the first coarse column bottom three-way valve into the second coarse column, open the second coarse column bottom three-way valve to collect waste liquid, about 5 column volumes, then cut the second coarse column bottom three-way valve into the third coarse column, open the third coarse column bottom three-way valve to collect waste liquid, about 5 column volumes, then cut the third coarse column bottom three-way valve into the fine column, open the fine column bottom three-way valve to collect waste liquid, close the sample column head valve, stop the sample column running, and open the first coarse column head valve at the same time. Change the mobile phase ratio to dichloromethane:methanol about 4:1 (V:V), run about 5 column volumes, then close the first and second coarse column head valves, stop the first and second coarse column running, and open the third coarse column head valve at the same time. Examine the product development of the fine column, according to the development, cut the fine column bottom three-way valve into the product collection pipeline, stop collecting after about 20 column volumes, open all column head valves, connect the washing liquid parallel pipeline, open the washing column packing, collect waste liquid, and the purification process is completed. Concentrate the product eluent containing to near dryness, cool to room temperature, disperse in the mobile phase solution, filter, wash the filter cake with cold mobile phase solution, and obtain 2.37 kg of white crystalline powder, which is obtained.

[0057] Performance test method

[0058] The purity of (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidinone obtained in the examples was tested (HPLC, area normalization method), and the liquid chromatograms of Examples 1-5 are shown in Figures 2-6

[0059] Performance test data ​

[0060] Table 1

[0061] Examples 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 multi-column combined medium-low pressure column chromatography apparatus, characterized in that, include: The system consists of 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 cleaning 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 in parallel. The cleaning 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) via a four-way valve and a two-way valve (11). The inlet end of column (3) is connected; the outlet end of the subdivision column (3) is connected to 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 loading 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 subdivision 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.

2. The multi-column combined medium-low pressure column chromatography apparatus 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 multi-column combined medium-low pressure column chromatography apparatus according to claim 1, characterized in that, The number of each of the sample loading column (1), coarse dividing column (2), and fine dividing column (3) is 1-5.

4. The multi-column combined medium-low pressure column chromatography apparatus according to claim 3, 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 multi-column combined medium-low pressure column chromatography apparatus according to claim 4, characterized in that, The loading column (1), coarse separation column (2), and fine separation column (3) are all filled with filler.

6. The multi-column combined medium-low pressure column chromatography apparatus according to claim 5, characterized in that, 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 The sample contains at least one of bonded silica gel (ODS), C8 bonded silica gel, C4 bonded silica gel, and aromatic bonded silica gel, preferably silica gel. The packing material in the loading column (1) has a mesh size of 100-400 mesh, the packing material in the coarse separation column (2) has a mesh size of 100-400 mesh, and the packing material in the fine separation column (3) has a mesh size of 300-1000 mesh.

7. A process for purifying (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution, wherein the process employs the apparatus described in any one of claims 1-6, characterized in that, 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 coarse separator (2) and the fine separator (3); 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. Stop the operation of the loading column (1) and the coarse separation column (2) in a timely manner, 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 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.

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

9. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 7, characterized in that, The total amount of packing material in the loading column (1), coarse separation column (2) and fine separation column (3) is less than 20% of the weight ratio of the reaction solution containing (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone.

10. The process for purifying the (S)-1-(carbamoyl)methyl-4-hydroxy-2-pyrrolidone reaction solution according to claim 7, 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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