Method for purifying diquafosol sodium

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a diquafosol sodium purification method which comprises the following steps: S1, dissolving a material, S2, eluting a solution obtained in the step S1 by using an elution solvent through a low-pressure preparation system filled with filler, and collecting a product component containing diquafosol sodium, and S3, carrying out nanofiltration concentration on the product component collected in the step S2, so as to obtain the diquafosol sodium. S4, adding ethanol into the concentrated solution for crystallization, and then filtering to obtain diquafosol sodium crystals; S5, drying, and recovering and reusing waste liquid through nanofiltration (such as cyclic utilization of the elution solvent), so that the waste liquid discharge and the use amount of a fresh solvent are reduced, the method is environment-friendly and economical, the elution solvent without strong acidity is adopted, and the cost is reduced. Equipment corrosion is avoided, the service life of production equipment is prolonged, and meanwhile, the consistency among batches is ensured through a gradient elution procedure and crystallization parameter optimization.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for purifying diquaphosphopropyl sodium. Background Technology

[0002] CN200780028646 describes a suitable method for the industrialized preparation of di(pyrimidine nucleoside 5'-)polyphosphates. The synthetic yield is 50.5%–94.3%, requiring a combination of separation and purification methods (e.g., recrystallization, ion exchange column chromatography, adsorption column chromatography, activated carbon column chromatography). The example describes dissolving the reaction solution in water, filtering to remove the precipitate, passing it through a strong cation exchange column (pK216 proton type), collecting the eluent, adjusting the base with triethylamine, adsorbing it onto an anion exchange column (IRA67-chloride type), eluting, concentrating and drying, then passing it through a strong cation exchange column (pK216 sodium type), collecting and concentrating the eluent, crystallizing with ethanol, and drying to obtain UP4U sodium salt. The purification process described requires three ion exchange operations, making it very complex.

[0003] CN201780066159 describes purification using chelating resin. Specifically, Up4U is dissolved in an aqueous solution or hydrophilic solvent, passed through a column packed with chelating resin, and the permeate is collected. The permeate is then acidified and crystallized to obtain UP4U. Activated carbon activated with zinc chloride is added, the activated carbon is removed by filtration, and the product is recrystallized to obtain UP4U. This purification method can yield a product with metal ion concentrations below 10 ppm. This method is complex and primarily describes the method for removing metal ions from the product.

[0004] CN202011503324 describes the process of dissolving UP4U-tri-n-pentanamine salt in purified water, eluting with ammonium bicarbonate solution by column chromatography, concentrating under reduced pressure, and then exchanging with a cation exchange resin to obtain the product through concentration and crystallization.

[0005] While existing technologies can obtain high-purity diquafosol sodium through purification, the purification process involves complex operations, high equipment occupancy, and low production efficiency due to the use of ion exchange resin column chromatography or combinations of multiple ion exchange resin column chromatography. Furthermore, the large-scale use of hydrochloric acid and high-concentration sodium chloride solutions for elution leads to equipment corrosion and generates large amounts of highly concentrated wastewater, resulting in high treatment costs and environmental pollution. Therefore, there is an urgent need for a new purification method for diquafosol sodium. Summary of the Invention

[0006] The purpose of this section is to outline some aspects of the embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0007] Therefore, the purpose of this invention is to provide a method for purifying sodium diquafosol, which reduces waste liquid discharge and fresh solvent consumption by recycling waste liquid through nanofiltration, such as the recycling of elution solvent. This method is environmentally friendly and economical. Furthermore, it uses a non-acidic elution solvent to avoid equipment corrosion and extend the life of production equipment. At the same time, it ensures batch-to-batch consistency through gradient elution procedures and optimized crystallization parameters.

[0008] To address the aforementioned technical problems, according to one aspect of the present invention, the present invention provides the following technical solution:

[0009] A method for purifying diquafosol sodium includes the following steps:

[0010] S1. Material dissolution: Dissolve the sample of diquaphos sodium before purification in purified water or a mixed solution of purified water and a hydrophilic solvent;

[0011] S2. Purification: The solution obtained in step S1 is passed through a low-pressure preparation system packed with packing material, eluted with an elution solvent, and the product fraction containing diquaphosphodium is collected.

[0012] S3. Concentration: The product components collected in step S2 are concentrated by nanofiltration. The concentrate is temporarily stored and then sent to a preparation tank to be prepared as an elution solvent.

[0013] S4. Crystallization and filtration: Add ethanol to the concentrate to crystallize, and then filter to obtain sodium diquaphosphoside crystals;

[0014] S5. Drying: Vacuum dry the filter cake to obtain high-purity diquarphosphodium sodium.

[0015] As a preferred embodiment of the purification method for diquaphosphodium described in this invention, the purity of the sample before purification is 88%, the purity of the purified product is ≥99.5%, the purity of the crystallized product is ≥99.9%, and the purity of each single impurity is ≤0.10%.

[0016] In a preferred embodiment of the purification method for diquaphospholine sodium described in this invention, the elution solvent in step S2 is a non-acidic solution, which is one or more of ammonium bicarbonate, phosphate buffer, or ammonium acetate buffer.

[0017] In a preferred embodiment of the diquafosol sodium purification method described in this invention, the waste liquid generated during the purification process is reused in the elution solvent preparation step after nanofiltration, thereby reducing waste liquid discharge and lowering costs.

[0018] In a preferred embodiment of the method for purifying sodium diquafosol according to the present invention, the packing material in step S2 is one of reversed-phase silica gel, ion exchange resin, or molecular sieve.

[0019] In a preferred embodiment of the method for purifying diquafosol sodium according to the present invention, the hydrophilic solvent in step S1 is one or more of methanol, ethanol, or acetonitrile.

[0020] In a preferred embodiment of the sodium diquafosol purification method described in this invention, the molecular weight cutoff of the nanofiltration concentration membrane in step S3 is 200-600 Da.

[0021] In a preferred embodiment of the purification method for diquaphosphopropyl sodium described in this invention, the ethanol in step S4 is added slowly dropwise, and the crystallization temperature is controlled at 20-30°C.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] The sample purity before purification was 88%. After purification using the process of this invention, the product purity was ≥99.5%, and after crystallization, the product purity was ≥99.9%, with a single impurity of ≤0.10%. The product yield was approximately 85%, which is very high. The eluent was not strongly acidic, and the equipment did not corrode. The waste liquid generated during the purification process can be reused in the eluent preparation step after nanofiltration, greatly reducing waste liquid, lowering costs, and being environmentally friendly. Attached Figure Description

[0024] To more clearly illustrate the technical solutions of the embodiments of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and detailed embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0025] Figure 1 This is a schematic flowchart of the purification method of the present invention;

[0026] Figure 2 This is a schematic diagram of the purification device of the present invention;

[0027] Figure 3 This is a schematic diagram of column chromatography for the present invention. Detailed Implementation

[0028] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0029] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0030] Secondly, the present invention is described in detail with reference to the schematic diagrams. When detailing the embodiments of the present invention, for ease of explanation, the cross-sectional views illustrating the device structure may be partially enlarged, not according to the usual scale. Furthermore, the schematic diagrams are merely examples and should not limit the scope of protection of the present invention. In addition, actual fabrication should include three-dimensional spatial dimensions of length, width, and depth.

[0031] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0032] This invention provides a method for purifying sodium diquafosol. By recycling waste liquid through nanofiltration (e.g., reusing the elution solvent), waste liquid discharge and fresh solvent consumption are reduced, making it environmentally friendly and economical. Furthermore, the use of a non-acidic elution solvent avoids equipment corrosion and extends the lifespan of production equipment. Simultaneously, batch-to-batch consistency is ensured through gradient elution procedures and optimized crystallization parameters. Please refer to [link to relevant documentation]. Figure 1-3 This includes the following steps:

[0033] S1. Material dissolution: Dissolve the sample of diquaphos sodium before purification in purified water or a mixed solution of purified water and a hydrophilic solvent;

[0034] S2. Purification: The solution obtained in step S1 is passed through a low-pressure preparation system packed with packing material, eluted with an elution solvent, and the product fraction containing diquaphosphodium is collected.

[0035] S3. Concentration: The product components collected in step S2 are concentrated by nanofiltration. The concentrate is temporarily stored and then sent to a preparation tank to be prepared as an elution solvent.

[0036] S4. Crystallization and filtration: Add ethanol to the concentrate to crystallize, and then filter to obtain sodium diquaphosphoside crystals;

[0037] S5. Drying: Vacuum dry the filter cake to obtain high-purity diquarphosphodium sodium;

[0038] Example:

[0039] Dissolving: Mix 5g of the raw material before purification, 3g of methanol, and 30g of purified water evenly and dissolve. The mixture is ready for purification.

[0040] Elution solution preparation: Elution solution 1: 79g ammonium bicarbonate, dissolved in 10L water until dissolved, set aside. Elution solution 2: 79g ammonium bicarbonate, dissolved in 2L water until dissolved, set aside.

[0041] Sample loading: Turn on the delivery pump and pump the purified sample into the chromatography column (300g packing material) at a flow rate of 10ml / min;

[0042] Purification: Elute under the following conditions -

[0043] time Flow rate 1 ratio of eluent 2 ratio of eluent 0 10ml / min 100％ 0％ 10 10ml / min 100 0％ 65 10ml / min 0 100 75 10ml / min 100 0 80 10ml / min 100 0

[0044] Collect and combine components with a product purity ≥ 95%.

[0045] Concentration: Nanofiltration, nanofiltration to a product concentration of approximately 100 g / L;

[0046] Crystallization and filtration: Add ethanol for crystallization, cool to 10-15℃, and stir for 1-2 hours. Filter; dry.

[0047] The filter cake was vacuum dried at a temperature of 55–65°C, yielding 4.25 g of product with a yield of 85% and a purity of 99.9%.

[0048] The column chromatography pattern is as follows: Figure 3 As shown;

[0049] Nanofiltration solution recovery:

[0050] Take a portion of the nanofiltration solution and add water to prepare eluent 1; take a portion of the nanofiltration solution and add water to prepare eluent 2.

[0051] 1. The column chromatography packing materials are: polystyrene quaternary ammonium salt powder anion exchange resin and ion exchange chromatography (IEX) resin;

[0052] 2. Sample loading conditions: Sample concentration 50-200 g / L, flow rate 0.1-1 BV / h;

[0053] 3. Eluent concentration: Eluent 1: 0.1M ammonium bicarbonate aqueous solution, Eluent 2: 0.5M ammonium bicarbonate aqueous solution;

[0054] 4. The elution conditions are as follows;

[0055] time Flow rate 1 ratio of eluent 2 ratio of eluent 0 0.1~1BV / h 100％ 0％ 10 0.1~1BV / h 100 0％ 65 0.1~1BV / h 0 100 75 0.1~1BV / h 100 0 80 0.1~1BV / / h 100 0

[0056] 5. Chromatography column diameter-to-height ratio: 1:5-1:20

[0057] 6. Sample concentration after nanofiltration concentration: 100-500 g / L.

[0058] Working Principle: This invention utilizes nanofiltration to recover and reuse waste liquid (e.g., recycling the eluent), reducing waste liquid discharge and fresh solvent consumption. It is environmentally friendly and economical, employing a non-acidic eluent to prevent equipment corrosion and extend equipment lifespan. Furthermore, optimized gradient elution procedures and crystallization parameters ensure batch-to-batch consistency. The initial sample purity is 88%, and after purification using this process, the product purity is ≥99.5%, and after crystallization, it is ≥99.9%, with a single impurity ≤0.10%. The product yield is approximately 85%, which is very high. The eluent is non-acidic, preventing equipment corrosion. Waste liquid generated during purification can be reused in the eluent preparation step after nanofiltration, significantly reducing waste liquid, lowering costs, and being environmentally friendly.

[0059] Although the present invention has been described above with reference to embodiments, various modifications can be made and components can be replaced with equivalents without departing from the scope of the invention. In particular, as long as there is no structural conflict, the features in the disclosed embodiments can be combined with each other in any manner. The lack of an exhaustive description of these combinations in this specification is merely for the sake of brevity and resource conservation. Therefore, the present invention is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

Claims

1. A method for purifying diquafosol sodium, characterized in that, Includes the following steps: S1. Material dissolution: Dissolve the sample of diquaphos sodium before purification in purified water or a mixed solution of purified water and a hydrophilic solvent; S2. Purification: The solution obtained in step S1 is passed through a low-pressure preparation system packed with packing material, eluted with an elution solvent, and the product fraction containing diquaphosphodium is collected. S3. Concentration: The product components collected in step S2 are concentrated by nanofiltration. The concentrate is temporarily stored and then sent to a preparation tank to be prepared as an elution solvent. S4. Crystallization and filtration: Add ethanol to the concentrate to crystallize, and then filter to obtain sodium diquaphosphoside crystals; S5. Drying: Vacuum dry the filter cake to obtain high-purity diquarphosphodium sodium.

2. The method for purifying diquafosol sodium according to claim 1, characterized in that, The purity of the sample before purification was 88%, the purity of the purified product was ≥99.5%, the purity of the crystallized product was ≥99.9%, and the purity of each single impurity was ≤0.10%.

3. The method for purifying diquafosol sodium according to claim 1, characterized in that, In step S2, the elution solvent is a non-acidic solution, which is one or more of ammonium bicarbonate, phosphate buffer, or ammonium acetate buffer.

4. The method for purifying diquafosol sodium according to claim 1, characterized in that, The waste liquid generated during the purification process is then nanofiltered and reused in the elution solvent preparation step, thereby reducing waste liquid discharge and lowering costs.

5. The method for purifying diquafosol sodium according to claim 1, characterized in that, The packing material in step S2 is one of reversed silica gel, ion exchange resin, or molecular sieve.

6. The method for purifying diquafosol sodium according to claim 1, characterized in that, In step S1, the hydrophilic solvent is one or more of methanol, ethanol, or acetonitrile.

7. The method for purifying diquafosol sodium according to claim 1, characterized in that, In step S3, the nanofiltration concentration membrane has a molecular weight cutoff of 200-600 Da.

8. The method for purifying diquafosol sodium according to claim 1, characterized in that, In step S4, ethanol is added slowly dropwise, and the crystallization temperature is controlled at 20-30℃.

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