A method for preparing sucrose octasulfate salt

Abstract

The application discloses a preparation method of sucrose octasulfate, which comprises the following steps: S1. under the catalysis of a phase transfer catalyst, reacting a material liquid A and a material liquid B in a micro-channel reactor to obtain a reaction liquid; the material liquid A comprises sucrose and a first solvent, and the material liquid B comprises pyridine sulfur trioxide and a second solvent; S2. extracting the reaction liquid in an alkali solution to obtain an extracted water phase; and S3. purifying the extracted water phase. The method adopts the micro-channel reactor, can avoid exposing personnel to an open reaction environment, and realizes safe production of the product; and the combination of the phase transfer catalyst and the continuous flow reaction is used, so that the reaction efficiency is very high, the residence time is short, the target product only stays for several minutes, the side reaction is less, the yield of the target product is high, the purity is high, the impurities are low, and the color is better, and the injection grade requirement is met.

Description

Technical Field

[0001] This invention specifically relates to a method for preparing sucrose octasulfate salt. Background Technology

[0002] Sucrose octasulfate is a novel pharmaceutical excipient used as a process excipient in liposome formulations. It is converted into triethylamine salt, and during formulation preparation, hydrogen ions are replaced to form sucrose octasulfate, creating a pH gradient that encapsulates the drug. Sucrose octasulfate achieves excellent encapsulation efficiency and offers advantages such as low toxicity and significant efficacy.

[0003] There are few existing methods for preparing potassium or sodium sucrose octasulfate. Chinese invention patents CN103193835A and CN108530498A disclose methods for preparing sodium and potassium sucrose octasulfate, respectively. These methods involve reacting sucrose with a triethylamine-sulfur trioxide complex, followed by pH adjustment with sodium hydroxide or potassium hydroxide to obtain sodium or potassium sucrose octasulfate. However, to prepare the intermediate product sulfur trioxide esterified sucrose, sulfur trioxide needs to be premixed with triethylamine, increasing the complexity of the reaction process. Furthermore, sulfur trioxide requires highly corrosion-resistant reaction equipment, is difficult to transport, and is prone to escaping during heated reactions, causing environmental pollution.

[0004] Chinese invention patent CN110981922A discloses a method for synthesizing potassium sucrose octasulfate, which involves reacting sucrose with chlorosulfonic acid in a pyridine solvent to produce potassium sucrose octasulfate. Although chlorosulfonic acid has high reactivity, it is highly corrosive and irritating, making it very unfriendly to equipment and human health.

[0005] Chinese invention patent CN 116262771A uses pyridine sulfur trioxide complex and sucrose as raw materials, with solvents such as acetone, tetrahydrofuran, and acetonitrile, and organic bases such as pyridine and dimethylpyridine as catalysts. The product is obtained through neutralization and recrystallization. Although this technology improves safety to some extent, with milder reaction conditions and reduced equipment requirements, it still uses a large amount of toxic and harmful organic solvents in the process, posing health risks to operators, especially during industrial production. Safety needs further improvement. Summary of the Invention

[0006] This invention overcomes the shortcomings of existing technologies regarding production complexity and safety, providing a method for preparing sucrose octasulfate salt. This method employs a microchannel reactor, avoiding personnel exposure to an open reaction environment and ensuring safe product production. Furthermore, the combination of a phase-transfer catalyst and continuous flow reaction results in extremely high reaction efficiency, short residence time (the target product resides for only a few minutes), and fewer side reactions, leading to high yield, high purity, low impurities, and better color of the target product, meeting injection-grade requirements.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] This invention provides a method for preparing sucrose octasulfate salt, which includes the following steps:

[0009] S1. Under the catalytic action of a phase transfer catalyst, feed solution A and feed solution B are reacted in a microchannel reactor to obtain a reaction solution; feed solution A includes sucrose and a first solvent, and feed solution B includes pyridine sulfur trioxide and a second solvent; the first solvent or the second solvent is a solvent that is immiscible with water; the mass ratio of sucrose to pyridine sulfur trioxide is 1:(3.8-4.8); the residence time of the reaction is 3-10 min;

[0010] S2. Extract the reaction solution with an alkaline solution to obtain the aqueous phase.

[0011] S3. Purify the extracted aqueous phase.

[0012] In this invention, the phase transfer catalyst can be a conventional surfactant in the art, such as triethylbenzylammonium chloride or tetrabutylammonium iodide.

[0013] In this invention, the amount and method of addition of the phase transfer catalyst can be conventionally selected in the art. For example, the phase transfer catalyst can be added to the feed solution A. The phase transfer catalyst can be 0.2%-0.5% of the mass of the sucrose, preferably 0.10%-0.17%.

[0014] In this invention, the preparation method of sucrose octasulfate salt does not require the use of an alkaline catalyst. The alkaline catalyst can be a commonly used catalyst in the preparation of sucrose octasulfate salt, such as pyridine or 2-methylpyridine.

[0015] In this invention, the concentration of sucrose in the feed solution A can be a conventional concentration in the art, preferably 0.2-0.3 g / mL, for example 0.25 g / mL.

[0016] In this invention, the feed rate of the feed liquid A can be a conventional flow rate that meets the residence time required for the reaction, preferably 2-7 mL / min, for example 2.03 mL / min, 4.07 mL / min, 5.91 mL / min or 6.78 mL / min.

[0017] In this invention, the concentration of pyridine sulfur trioxide in the feed solution B can be a conventional concentration in the art, preferably 0.2-0.3 g / mL, for example 0.25 g / mL.

[0018] In this invention, the feed rate of the feed liquid B can be a conventional flow rate that meets the residence time required for the reaction, preferably 7-28 mL / min, for example 7.97 mL / min, 15.93 mL / min, 26.56 mL / min or 27.42 mL / min.

[0019] In this invention, the first solvent or the second solvent is a solvent that is immiscible with water, which facilitates subsequent extraction operations.

[0020] In this invention, the first solvent or the second solvent may be a conventional ester solvent, such as ethyl acetate.

[0021] In this invention, the first solvent or the second solvent may be a conventional hydrocarbon solvent, preferably a C6-C8 hydrocarbon solvent, such as n-hexane.

[0022] In this invention, neither the first solvent nor the second solvent is tetrahydrofuran, acetonitrile, or acetone.

[0023] In this invention, when the sucrose cannot be completely dissolved in the first solvent or the second solvent, the sucrose is preferably micronized sucrose powder.

[0024] The particle size of the sucrose powder may not exceed 200 mesh, for example, 200-300 mesh. Using micronized sucrose powder can not only prevent equipment blockage, but also increase the contact area between the solid and liquid phases.

[0025] In this invention, when the sucrose can be completely dissolved in the first solvent or the second solvent, there are no special requirements for the particle size of the sucrose.

[0026] In this invention, the mass ratio of sucrose to pyridine sulfur trioxide can be 1:3.92, 1:4.00, 1:4.20, 1:4.50, or 1:4.64. Preferably, it is 1:(4.0-4.8), and more preferably, it is 1:(4.5-4.8).

[0027] In this invention, the microchannel reactor can be a conventional type of microchannel reactor in the art, such as the Corning Microchannel Reactor G1.

[0028] In this invention, the reaction temperature can be 120-150℃, for example 120℃, 130℃, 145℃ or 150℃.

[0029] In this invention, the residence time of the reaction can be 3 min, 5 min, 7 min, 8 min or 10 min.

[0030] In this invention, the back pressure of the reaction can be 4-6 bar.

[0031] In this invention, the reaction solution is generally obtained by filtering the materials obtained from the reaction.

[0032] The filtration process can be a conventional process. The filtration temperature is lower than the reaction temperature, typically 30-40°C. The equipment used for filtration can be conventional equipment, such as a continuous filter.

[0033] In this invention, the extraction operation and conditions can be conventionally selected in the art.

[0034] In this invention, the type of alkali in the alkaline solution can be conventionally selected in the art, preferably an alkali containing an alkali metal, such as potassium hydroxide or sodium hydroxide.

[0035] In this invention, the concentration of the alkaline solution can be conventionally selected in the art, preferably 20-40%, for example 30% or 35%.

[0036] In this invention, the pH value of the extraction aqueous phase can be 8.5-10.5, for example 8.5, 9.5 or 10.0.

[0037] In this invention, the purification operations and conditions can be conventionally selected in the art, and may include steps such as decolorization, ultrafiltration, crystallization, centrifugation, and drying.

[0038] The decolorization process can be a conventional process. For example, activated carbon adsorption can be used.

[0039] The activated carbon adsorption process conditions can be conventional. The activated carbon adsorption temperature can be 60-70℃, for example, 60℃, 65℃, or 70℃. The activated carbon adsorption time can be 0.8-1.2h, for example, 1h. The amount of activated carbon added can be 0.15wt%-0.25wt% of the extraction aqueous phase, for example, 0.2wt%. The above percentages mean the percentage of the mass of activated carbon to the mass of the extraction aqueous phase.

[0040] The ultrafiltration process can be a conventional process. Ultrafiltration can be performed using an ultrafiltration membrane. The molecular weight cutoff of the ultrafiltration membrane can be 5kD-10kD. The material of the ultrafiltration membrane can be a conventional material, such as PES, nylon 66, modified cellulose, or PP. The modified cellulose can be cellulose acetate or cellulose nitrate, etc.

[0041] The crystallization process can be a conventional process. The crystallization temperature can be 10-15℃. The equipment used for crystallization can be conventional equipment, such as a continuous crystallizer.

[0042] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0043] The reagents and raw materials used in this invention are all commercially available.

[0044] The positive and progressive effects of this invention are as follows:

[0045] (1) The present invention uses a microchannel reactor, which can avoid personnel being exposed to an open reaction environment and achieve safe production of products;

[0046] (2) This invention uses a microchannel reactor with no backmixing of materials and utilizes the combination of phase transfer catalyst and continuous flow reaction to achieve very high reaction efficiency, short residence time, target product residence time of only a few minutes, fewer side reactions, control of impurities such as microorganisms and endotoxins, resulting in high product yield, high purity, low impurities, better color, and meeting injection grade requirements.

[0047] (3) The present invention uses ester solvents or hydrocarbon solvents with lower toxicity and higher safety, which is more in line with the concept of green chemistry;

[0048] (4) The present invention uses a solid phase transfer catalyst, which can avoid the use of alkaline catalysts such as pyridine or 2-methylpyridine with strong odor, and is safer;

[0049] (5) The process of this invention is simple to operate and easy to industrialize. Attached Figure Description

[0050] Figure 1 Characteristic chromatogram of potassium sucrose octasulfate standard;

[0051] Figure 2 Characteristic chromatogram of potassium sucrose heptasulfate standard. Detailed Implementation

[0052] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments, unless otherwise specified, are performed according to the conventional methods and conditions described above, or as selected in the product manual.

[0053] The specific model of the microchannel reactor used in the following examples and comparative examples is the Corning Microchannel Reactor G1. The single silicon carbide module has a liquid holding volume of approximately 8.3 ml, and the module's interior consists of numerous heart-shaped structural units. The maximum reaction pressure can reach 18 bar, and the heat exchange area per unit volume of the reaction liquid can reach 2500 m². 2 / m 3 The overall heat transfer coefficient can reach 1700kW / m³. 3 • K. The following examples and comparative examples use 12 silicon carbide modules with a total liquid holding volume of approximately 100 ml.

[0054] Example 1

[0055] The continuous preparation method of high-purity injection-grade potassium sucrose octasulfate is shown in Table 1, and the details are as follows:

[0056] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with n-hexane, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0057] S2. Prepare a solution of pyridine sulfur trioxide and n-hexane to a concentration of 0.2 g / mL, which is called solution B.

[0058] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding capacity of 10L to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.92, and the residence time is 3min. That is, the feed rate of feed solution A is 6.78mL / min, the feed rate of feed solution B is 26.56mL / min, and a back pressure valve is set at 4bar, with a reaction temperature of 120℃.

[0059] S4. Collect 2L of the reaction solution after 1 hour of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0060] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0061] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0062] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 275g of white crystalline powder.

[0063] Example 2

[0064] The continuous preparation method of high-purity injection-grade potassium sucrose octasulfate is shown in Table 1, and the details are as follows:

[0065] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with n-hexane, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0066] S2. Prepare a solution of pyridine sulfur trioxide and n-hexane to a concentration of 0.2 g / mL, which is called solution B.

[0067] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.92, and the residence time is 10 min. That is, the feed rate of feed solution A is 2.03 mL / min, the feed rate of feed solution B is 7.97 mL / min, and a back pressure valve is set at 4 bar, and the reaction temperature is 120℃.

[0068] S4. Collect 2L of the reaction solution after 200min of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0069] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0070] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0071] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 278g of white crystalline powder.

[0072] Example 3

[0073] The continuous preparation method of high-purity injection-grade potassium sucrose octasulfate is shown in Table 1, and the details are as follows:

[0074] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with n-hexane, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0075] S2. Prepare a solution of pyridine sulfur trioxide and n-hexane to a concentration of 0.2 g / mL, which is called solution B.

[0076] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.92, and the residence time is 5 min. That is, the feed rate of feed solution A is 4.07 mL / min, the feed rate of feed solution B is 15.93 mL / min, and a back pressure valve is set at 4 bar, and the reaction temperature is 120℃.

[0077] S4. Collect 2L of the reaction solution after 100min of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0078] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0079] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0080] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 277g of white crystalline powder.

[0081] Example 4

[0082] The continuous preparation method of high-purity injection-grade potassium sucrose octasulfate is shown in Table 1, and the details are as follows:

[0083] S1. Prepare a solution with a mass concentration of 0.25 g / mL by mixing micronized sucrose powder (200 mesh) with ethyl acetate, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0084] S2. Prepare a solution of pyridine sulfur trioxide and ethyl acetate to a concentration of 0.25 g / mL, which is called solution B.

[0085] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.92, and the residence time is 3 min. That is, the feed rate of feed solution A is 6.78 mL / min, the feed rate of feed solution B is 26.56 mL / min, and a back pressure valve is set at 4 bar, with a reaction temperature of 120℃.

[0086] S4. Collect 2L of the reaction solution after 1 hour of reaction, pass it into an extractor, add 35% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0087] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0088] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0089] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 337g of white crystalline powder.

[0090] Example 5

[0091] The continuous preparation method of high-purity injection-grade potassium sucrose octasulfate is shown in Table 1, and the details are as follows:

[0092] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with n-hexane, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0093] S2. Prepare a solution of pyridine sulfur trioxide and n-hexane to a concentration of 0.2 g / mL, which is called solution B.

[0094] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:4.64, and the residence time is 3 min. That is, the feed rate of feed solution A is 5.91 mL / min, the feed rate of feed solution B is 27.42 mL / min, and a back pressure valve is set at 4 bar, with a reaction temperature of 120℃.

[0095] S4. Collect 2L of the reaction solution after 1 hour of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 10.0.

[0096] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0097] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0098] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 281g of white crystalline powder.

[0099] Example 6

[0100] The continuous preparation method of high-purity injection-grade potassium sucrose octasulfate is shown in Table 1, and the details are as follows:

[0101] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with n-hexane, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0102] S2. Prepare a solution of pyridine sulfur trioxide and n-hexane to a concentration of 0.2 g / mL, which is called solution B.

[0103] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.92, and the residence time is 3 min. That is, the feed rate of feed solution A is 6.78 mL / min, the feed rate of feed solution B is 26.56 mL / min, and a back pressure valve is set at 4 bar, with a reaction temperature of 150℃.

[0104] S4. Collect 2L of the reaction solution after 1 hour of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0105] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0106] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0107] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 274g of white crystalline powder.

[0108] Comparative Example 1

[0109] The preparation method of potassium sucrose octasulfate is shown in Table 1. The main difference from Example 1 is that hexane is replaced with acetone in this comparative example, as detailed below:

[0110] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with acetone, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0111] S2. Prepare a 0.2 g / mL solution of pyridine sulfur trioxide and acetone, i.e., solution B.

[0112] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.92, and the residence time is 3 min. That is, the feed rate of feed solution A is 6.78 mL / min, the feed rate of feed solution B is 26.56 mL / min, and a back pressure valve is set at 4 bar, with a reaction temperature of 120℃.

[0113] S4. Collect 2L of the reaction solution after 1 hour of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0114] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0115] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0116] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 257g of white crystalline powder.

[0117] Comparative Example 2

[0118] The preparation method of potassium sucrose octasulfate is shown in Table 1. The main difference from Example 1 is that this comparative example uses a one-pot reaction of sucrose and pyridine sulfur trioxide, as detailed below:

[0119] S1. Add 2.4L of n-hexane, 120g of micronized sucrose powder (200 mesh), 470g of pyridine sulfur trioxide, and 2.4g of triethylbenzylammonium chloride to the reactor.

[0120] S2. Pressurize the reactor to 4 bar, heat it to 120°C and keep it at that temperature for about 1 hour. Filter to obtain the reaction solution.

[0121] S3. The reaction solution enters the extractor, potassium hydroxide solution is added for extraction, and the lower aqueous phase is obtained with pH=9.5.

[0122] S4. Add 0.2wt% activated carbon to the lower aqueous phase and adsorb at 60℃ for 1 hour. Filter to obtain the decolorized solution;

[0123] S5. The decolorizing liquid is treated by an ultrafiltration unit with an ultrafiltration membrane that has a molecular weight cutoff of 5KD and is made of PES.

[0124] S6. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 402g of off-white crystalline powder.

[0125] Comparative Example 3

[0126] The preparation method of potassium sucrose octasulfate is shown in Table 1. The main difference from Example 1 is that the ratio of sucrose to pyridine sulfur trioxide in this comparative example is reduced to 1:3.6, as detailed below:

[0127] S1. Prepare a solution with a mass concentration of 0.2 g / mL by mixing micronized sucrose powder (200 mesh) with n-hexane, add 0.2% of triethylbenzylammonium chloride by mass of sucrose, and stir to obtain solution A.

[0128] S2. Prepare a solution of pyridine sulfur trioxide and n-hexane to a concentration of 0.2 g / mL, which is called solution B.

[0129] S3. Feed solutions A and B are introduced into a microchannel reactor with a holding volume of 100 mL to carry out the reaction, and then filtered to obtain the reaction solution. During the reaction, the mass ratio of sucrose to pyridine sulfur trioxide is 1:3.6, and the residence time is 3 min. That is, the feed rate of feed solution A is 7.25 mL / min, the feed rate of feed solution B is 26.09 mL / min, and a back pressure valve is set at 4 bar, and the reaction temperature is 120℃.

[0130] S4. Collect 2L of the reaction solution after 1 hour of reaction, pass it into an extractor, add 30% potassium hydroxide solution for extraction, and adjust the pH of the lower extraction aqueous phase to 9.5.

[0131] S5. Add 0.2wt% activated carbon to the lower extraction aqueous phase, adsorb at 60℃ for 1h, filter, and obtain the decolorized solution.

[0132] S6. The decolorizing liquid is treated by ultrafiltration unit. The ultrafiltration membrane has a molecular weight cutoff of 5KD and the membrane material is PES.

[0133] S7. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 298g of white crystalline powder.

[0134] Comparative Example 4

[0135] The preparation method of potassium sucrose octasulfate is shown in Table 1. The main difference from Example 1 is that this comparative example uses a one-pot reaction of sucrose and pyridine sulfur trioxide, as detailed below:

[0136] S1. Add 2.4L of n-hexane, 120g of micronized sucrose powder (200 mesh), 470g of pyridine sulfur trioxide, and 2.4g of triethylbenzylammonium chloride to the reactor.

[0137] S2. Pressurize the reactor to 4 bar, heat it to 150°C and keep it at that temperature for about 1 hour. Filter to obtain the reaction solution.

[0138] S3. The reaction solution enters the extractor, potassium hydroxide solution is added for extraction, and the lower aqueous phase is obtained with pH=9.5.

[0139] S4. Add 0.2wt% activated carbon to the lower aqueous phase and adsorb at 60℃ for 1 hour. Filter to obtain the decolorized solution;

[0140] S5. The decolorizing liquid is treated by an ultrafiltration unit with an ultrafiltration membrane that has a molecular weight cutoff of 5KD and is made of PES.

[0141] S6. Cool to 10℃ to crystallize, centrifuge, and dry to obtain 407g of off-white crystalline powder.

[0142] Table 1 lists the main conditions in Examples 1-6 and Comparative Examples 1-4.

[0143] Example 1 3 120 1:3.92 n-Hexane Example 2 10 120 1:3.92 n-Hexane Example 3 5 120 1:3.92 n-Hexane Example 4 3 120 1:3.92 Ethyl acetate Example 5 3 120 1:4.64 n-Hexane Example 6 3 150 1:3.92 Ethyl acetate Comparative Example 1 3 120 1:3.92 acetone Comparative Example 2 One-pot method 120 1:3.92 n-Hexane Comparative Example 3 3 120 1:3.6 n-Hexane Comparative Example 4 One-pot method 150 1:3.92 n-Hexane

[0144] Example 1

[0145] Regarding the yield of potassium sucrose octasulfate, in the reaction system of this invention, if pyridine sulfur trioxide is in excess, the theoretical yield should be calculated based on the mass of sucrose.

[0146] For example, the mass of sucrose is M1, and its molecular weight is 342.17, while the molecular weight of the target product, potassium sucrose octasulfate, is 1287.52.

[0147] Theoretical material receiving quantity M2 = (M1 ÷ 342.17) × 1287.52.

[0148] Yield = Actual received amount M3 ÷ Theoretical received amount M2 × 100%.

[0149] For example, in Example 1, 81.4g of sucrose participated in the reaction in 2L of feed solution, with a theoretical yield of 306g and an actual yield of 275g, resulting in a yield of 90%. The yields of the other examples and comparative examples are shown in Table 4 below.

[0150] Example 2

[0151] The specific test procedure for determining the purity of potassium sucrose octasulfate is as follows:

[0152] (1) Solution preparation

[0153] Test solution: Weigh about 50 mg of this product accurately, put it in a 20 mL volumetric flask, add water to dissolve and dilute to the mark, shake well, accurately measure 1 mL of the above solution, put it in a 50 mL volumetric flask, dilute with water to the mark, shake well to obtain the test solution.

[0154] Reference stock solution: Weigh 50 mg of potassium sucrose octate reference standard accurately, dissolve and dilute to the mark with water in a 20 mL volumetric flask, and shake well to obtain the reference stock solution; accurately measure 1 mL of the above solution, place it in a 25 mL volumetric flask, dilute to the mark with water, and shake well to obtain the reference stock solution.

[0155] Reference solution 1: Accurately measure 1 mL of the reference stock solution and place it in a 10 mL volumetric flask. Dilute with water to the mark to obtain the solution.

[0156] Reference solution 2: Accurately measure 3 mL of the reference stock solution and place it in a 10 mL volumetric flask. Dilute with water to the mark to obtain the solution.

[0157] Reference solution 3: Accurately measure 5 mL of the reference stock solution and place it in a 10 mL volumetric flask. Dilute with water to the mark to obtain the solution.

[0158] Reference solution 4: Accurately measure 7 mL of the reference stock solution and place it in a 10 mL volumetric flask. Dilute with water to the mark to obtain the solution.

[0159] Reference solution 5: This is obtained by taking the reference stock solution.

[0160] (2) Set the chromatographic conditions, as shown in Table 2.

[0161] Table 2 Chromatographic conditions

[0162]

[0163] Set gradient elution conditions as shown in Table 3

[0164] Table 3 Gradient elution conditions

[0165] 0 5 95 5 40 60 7 40 60 8 60 40 14 60 40 15 5 95 25 5 95

[0166] (3) Detection and analysis:

[0167] Accurately measure 5 μL each of the above reference solution and test solution and inject them into the liquid chromatograph, then record the chromatograms.

[0168] (4) Calculation of results:

[0169] The regression equation is calculated by using the logarithm of the concentration of the reference solution and the corresponding logarithm of the peak area, resulting in a linear equation of concentration versus peak area, such as: y = ax + b. Substituting the peak area of ​​the sample solution, the concentration 'a' of potassium sucrose octasulfate in the sample solution can be calculated. Based on the sample preparation method, the mass m1 of potassium sucrose octasulfate in the sample can be calculated. The purity of the product is obtained by comparing this mass with the sample weight m0.

[0170] For example, in Example 1, the purity of potassium sucrose octasulfate was 99.8%, and the content of the impurity potassium sucrose heptasulfate was <0.01%. The purity in the other examples and comparative examples is shown in Table 4 below. The characteristic chromatogram of the potassium sucrose octasulfate standard is shown below. Figure 1 As shown, the characteristic retention time is 9.35 min; the characteristic chromatogram of potassium sucrose heptasulfate standard is as follows. Figure 2 As shown, the feature retention time is 7.93 min.

[0171] Example 3

[0172] Regarding the clarity and color of the solution prepared from the obtained potassium sucrose octasulfate.

[0173] Test method: Take 1g of the prepared potassium sucrose octasulfate and add it to a Nessler tube, dissolving and diluting to 25mL. Test according to General Chapters 0901 / 0902 of the 2020 edition of the Chinese Pharmacopoeia. For example, in Example 1, the clarity and color of the solution were clear and colorless. The clarity and color of the remaining examples and comparative examples are shown in Table 4 below.

[0174] Table 4 lists the effects of Examples 1-6 and Comparative Examples 1-4.

[0175]

[0176] Compared to Example 1, Comparative Example 1 used acetone as a solvent, resulting in a significant decrease in product purity. This is because the cation phase transfer catalyst of the present invention exhibits higher catalytic efficacy in low-polarity solvents but lower activity in high-polarity solvents such as acetone. Furthermore, using acetone as a solvent increases the difficulty of subsequent extraction and purification due to its miscibility with water.

[0177] Compared to Example 1, Comparative Examples 2 and 4 used a one-pot reaction. Although the reaction rate could be increased by raising the reaction temperature through pressure, allowing the reaction to be completed in 1 hour, from a reaction principle perspective, the product generated in a one-pot reaction would be continuously heated in the reaction system until the reaction was terminated, which would increase the content of the impurity potassium sucrose heptasulfate. In contrast, Example 1 used a microchannel continuous flow device, which prevented backmixing of materials. The target product only stayed in the reaction system for a few minutes, resulting in fewer side reactions, higher product purity, and better color.

[0178] Compared with Example 1, the mass ratio of sucrose to pyridine sulfur trioxide in Comparative Example 3 was only 1:3.6. The pyridine sulfur trioxide was lower than the theoretical value, which caused sucrose to be in excess in the reaction system, resulting in a significant decrease in product purity and a significant increase in the content of potassium heptasulfate, an impurity.

Claims

1. A method for preparing sucrose octasulfate salt, characterized in that, It includes the following steps: S1. Under the catalysis of a phase transfer catalyst, feed solution A and feed solution B are reacted in a microchannel reactor to obtain a reaction solution; feed solution A includes sucrose and a first solvent, and feed solution B includes pyridine sulfur trioxide and a second solvent; the first solvent is ethyl acetate and / or n-hexane, and the second solvent is ethyl acetate and / or n-hexane; the mass ratio of sucrose to pyridine sulfur trioxide is 1:(3.8-4.8); the residence time of the reaction is 3-10 min; the phase transfer catalyst is triethylbenzylammonium chloride; S2. Extract the reaction solution with an alkaline solution to obtain an aqueous extraction phase; S3. Purify the extracted aqueous phase; In the preparation method of the sucrose octasulfate salt, no alkaline catalyst is used; the alkaline catalyst is pyridine or 2-methylpyridine.

2. The method for preparing sucrose octasulfate salt as described in claim 1, characterized in that, The mass ratio of sucrose to pyridine sulfur trioxide is 1:(4.0-4.8); And / or, the residence time of the reaction is 3 min, 5 min, 7 min, 8 min or 10 min; And / or, the temperature of the reaction is 120-150°C.

3. The method for preparing sucrose octasulfate salt as described in claim 2, characterized in that, The mass ratio of sucrose to pyridine sulfur trioxide is 1:(4.5-4.8); And / or, the reaction temperature is 120°C, 130°C, 145°C, or 150°C.

4. The method for preparing sucrose octasulfate salt as described in claim 3, characterized in that, The mass ratio of sucrose to pyridine sulfur trioxide is 1:4.

64.

5. The method for preparing sucrose octasulfate salt as described in claim 1, characterized in that, The sucrose is micronized sucrose powder; And / or, the back pressure of the reaction is 4-6 bar; And / or, the concentration of sucrose in the feed solution A is 0.2-0.3 g / mL; And / or, the feed rate of the feed solution A is 2-7 mL / min; And / or, the concentration of pyridine sulfur trioxide in the feed solution B is 0.2-0.3 g / mL; And / or, the feed rate of the feed liquid B is 7-28 mL / min.

6. The method for preparing sucrose octasulfate salt as described in claim 5, characterized in that, The particle size of the sucrose powder is no greater than 200 mesh; And / or, the concentration of sucrose in the feed solution A is 0.25 g / mL; And / or, the feed rate of the feed solution A is 2.03 mL / min, 4.07 mL / min, 5.91 mL / min or 6.78 mL / min; And / or, the concentration of pyridine sulfur trioxide in the feed solution B is 0.25 g / mL; And / or, the feed rate of the feed solution B is 7.97 mL / min, 15.93 mL / min, 26.56 mL / min or 27.42 mL / min.

7. The method for preparing sucrose octasulfate salt as described in claim 6, characterized in that, The sucrose powder has a particle size of 200-300 mesh.

8. The method for preparing sucrose octasulfate salt as described in claim 1, characterized in that, The reaction solution is obtained by filtering the material obtained from the reaction; And / or, the type of base in the alkaline solution is an alkali containing an alkali metal; And / or, the concentration of the alkaline solution is 20-40%; And / or, the pH of the extraction aqueous phase is 8.5-10.5; And / or, the purification process includes: decolorization, ultrafiltration, crystallization, centrifugation, and drying.

9. The method for preparing sucrose octasulfate salt as described in claim 8, characterized in that, The filtration temperature is 30-40℃; And / or, the type of alkali in the alkaline solution is potassium hydroxide or sodium hydroxide; And / or, the concentration of the alkaline solution is 30% or 35%; And / or, the pH of the extraction aqueous phase is 8.5, 9.5, or 10.0; And / or, the decolorization is a decolorization using activated carbon adsorption; And / or, the ultrafiltration is ultrafiltration performed using an ultrafiltration membrane; And / or, the crystallization temperature is 10-15°C.

10. The method for preparing sucrose octasulfate salt as described in claim 9, characterized in that, The temperature at which the activated carbon adsorbs is 60-70℃; And / or, the adsorption time of the activated carbon is 0.8-1.2 h; And / or, the amount of activated carbon added is 0.15wt%-0.25wt% of the extraction aqueous phase, where the above percentage means the percentage of the mass of activated carbon to the mass of the extraction aqueous phase; And / or, the molecular weight cutoff of the ultrafiltration membrane is 5 kD-10 kD; And / or, the material of the ultrafiltration membrane includes PES, nylon 66, modified cellulose, or PP.

11. The method for preparing sucrose octasulfate salt as described in claim 10, characterized in that, The temperature at which the activated carbon adsorbs is 60℃, 65℃, or 70℃. And / or, the activated carbon adsorption time is 1 h; And / or, the amount of activated carbon added is 0.2 wt% of the aqueous phase used for extraction; And / or, the modified cellulose is cellulose acetate or cellulose nitrate.

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