Process for the synthesis of sucrose octasulfate

Abstract

This invention provides a process for synthesizing sucrose octasulfate salt, specifically relating to the pharmaceutical field. The process involves heating 30-40g of sulfur trioxide pyridine and 15-25g of pyridine to 35-40°C, stirring and mixing at 200-300 rpm, and then adding 10-15g of sucrose. Nitrogen gas is then introduced, and the temperature is slowly raised to 75-80°C, reacting for 5-7 hours. Pyridine is then separated using a reflux condenser, and 50-150ml of distilled water is added to dissolve the residual solid. The mixture is then decolorized with diatomaceous earth and filtered to obtain a filtrate. Potassium hydroxide solution is added to the filtrate until the pH reaches 9-12, followed by the addition of anhydrous ethanol. The mixture is cooled at 0-5°C to crystallize and obtain a crude product. Recrystallization is then performed for 6-7 hours, followed by solid-liquid separation to obtain a filter cake. The filter cake is then vacuum-dried at 70-80°C for 20-30 minutes to obtain the target product. This invention features simple synthesis steps, high reaction efficiency, and high product purity. Furthermore, the separation and purification operations are simple, effectively improving the yield.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a process for synthesizing sucrose octasulfate salt. Background Technology

[0002] Sucrose octasulfate salt is a C64-32 ... 12 H 14 O 35 S8-R8, where R represents elements such as Na, K, and Al. Sucrose octasulfate salts have wide applications in pharmaceutical synthesis. Composed of sulfate groups and sucrose molecules, sucrose octasulfate salts possess good stability and solubility, significantly improving the yield and purity of pharmaceutical synthesis reactions. However, the yield and impurities of existing sucrose octasulfate salt synthesis methods still require further improvement. Patent application number 202111527736.0 discloses a method for synthesizing sucrose octasulfate salts. This involves esterifying sucrose and sulfur trioxide pyridine under a catalyst to obtain a reaction solution. The solvent layer in the reaction solution is removed, and the pH is adjusted to salt formation using an inorganic alkali solution. The solid precipitated upon cooling is the crude sucrose octasulfate salt. The crude sucrose octasulfate salt is then crystallized in purified water and vacuum dried to obtain purified sucrose octasulfate salt. This method offers mild reaction conditions, simple operation, high yield, and high purity, but the purity and impurity content of the product still need improvement. Summary of the Invention

[0003] The purpose of this invention is to provide a process for synthesizing sucrose octasulfate salt with high synthesis yield and low impurity content.

[0004] This invention provides the following technical solution:

[0005] A process for synthesizing sucrose octasulfate salt, comprising the following steps:

[0006] S1. Heat 30-40g of sulfur trioxide pyridine and 15-25g of pyridine to 30-40℃, stir and mix at 200-300r / min, and add 10-15g of sucrose;

[0007] S2. Then, nitrogen gas is introduced and the temperature is slowly raised to 75-80°C, and the reaction is carried out for 5-7 hours.

[0008] S3. Then, pyridine is separated by reflux condenser, and 50-150 ml of distilled water is added to dissolve the residual solid. The filtrate is obtained by decolorization and filtration with diatomaceous earth.

[0009] S4. Add potassium hydroxide solution to the filtrate until the pH is 9-12, then add anhydrous ethanol, and cool at 0-5°C to crystallize and obtain crude product.

[0010] S5. Then recrystallize for 6-7 hours, separate the solid and liquid to obtain a filter cake, and vacuum dry the filter cake at 70℃-80℃ for 20-30 minutes to obtain the target product.

[0011] Preferably, in step S1, 35g of sulfur trioxide pyridine and 20g of pyridine are heated to 35°C, stirred and mixed at 220r / min, and 12g of sucrose is added.

[0012] Preferably, in step S2, nitrogen gas is then introduced and the temperature is slowly raised to 78°C, and the reaction is carried out for 6 hours.

[0013] Preferably, in step S3, pyridine is then separated through a reflux condenser, and 100 ml of distilled water is added to dissolve the remaining solid. The filtrate is then obtained by decolorization with diatomaceous earth and filtration.

[0014] Preferably, in step S4, potassium hydroxide solution is added to the filtrate until the pH is 9-12, then anhydrous ethanol is added, and the mixture is cooled at 0°C to crystallize and obtain the crude product.

[0015] Preferably, a 20% potassium hydroxide solution is added until the pH reaches 10.

[0016] Preferably, in step S5, the product is recrystallized for 6.5 hours, and the solid-liquid separation is performed to obtain a filter cake. The filter cake is then vacuum dried at 75°C for 25 minutes to obtain the target product.

[0017] The beneficial effects of this invention are:

[0018] The present invention has a simple synthesis procedure and high reaction efficiency, which can effectively reduce the breakage of glycosidic bonds in sucrose molecules, thereby improving product purity; and the separation and purification operation is simple, which can effectively improve the yield. Detailed Implementation

[0019] Example 1:

[0020] A process for synthesizing sucrose octasulfate salt is as follows: 30g of sulfur trioxide pyridine and 15g of pyridine are heated to 30℃ and stirred at 200r / min. 10g of sucrose is added. Then, nitrogen gas is introduced and the temperature is slowly raised to 75℃, and the reaction is carried out for 5h. The pyridine is then separated through a reflux condenser. 50ml of distilled water is added to dissolve the residual solid, and the solution is filtered through diatomaceous earth for decolorization to obtain the filtrate. Potassium hydroxide solution is added to the filtrate until the pH reaches 9, and then anhydrous ethanol is added. The solution is cooled at 0℃ to crystallize and obtain the crude product. Recrystallization is then carried out for 6h, and the solid and liquid are separated to obtain the filter cake. The filter cake is dried under vacuum at 70℃ for 20min to obtain 27.9g of potassium sucrose octasulfate with a purity of 99.3% and a yield of 93%.

[0021] Example 2:

[0022] A process for synthesizing sucrose octasulfate salt is as follows: 31g of sulfur trioxide pyridine and 17g of pyridine are heated to 32℃ and stirred at 210r / min. 10-15g of sucrose is added. Then, nitrogen gas is introduced and the temperature is slowly raised to 77℃, and the reaction is carried out for 6 hours. The pyridine is then separated through a reflux condenser. 80ml of distilled water is added to dissolve the residual solid, and the solution is filtered through diatomaceous earth for decolorization to obtain the filtrate. Potassium hydroxide solution is added to the filtrate until the pH reaches 10, and then anhydrous ethanol is added. The solution is cooled at 1℃ to crystallize and obtain the crude product. Recrystallization is then carried out for 6.5 hours, and solid-liquid separation is performed to obtain the filter cake. The filter cake is vacuum dried at 73℃ for 22 minutes to obtain 28.8g of potassium sucrose octasulfate with a purity of 98.7% and a yield of 92%.

[0023] Example 3:

[0024] A process for synthesizing sucrose octasulfate salt is as follows: 35g of sulfur trioxide pyridine and 20g of pyridine are heated to 35℃ and stirred at 220r / min. 12g of sucrose is added. Then, nitrogen gas is introduced and the temperature is slowly raised to 78℃, and the reaction is carried out for 6h. Pyridine is then separated through a reflux condenser. 100ml of distilled water is added to dissolve the residual solid. The solution is decolorized by diatomaceous earth and filtered to obtain the filtrate. 20% potassium hydroxide solution is added to the filtrate until the pH reaches 10. Then, anhydrous ethanol is added, and the solution is cooled at 0℃ to crystallize and obtain the crude product. The solution is then recrystallized for 6.5h, and the solid and liquid are separated to obtain the filter cake. The filter cake is vacuum dried at 75℃ for 25min to obtain 33.2g of potassium sucrose octasulfate with a purity of 99.7% and a yield of 94%.

[0025] Example 4:

[0026] A process for synthesizing sucrose octasulfate salt is as follows: 35g of sulfur trioxide pyridine and 20g of pyridine are heated to 36℃ and stirred at 230r / min. 13g of sucrose is added. Then, nitrogen gas is introduced and the temperature is slowly raised to 77℃, and the reaction is carried out for 6 hours. Pyridine is then separated through a reflux condenser. 100ml of distilled water is added to dissolve the residual solid, and the solution is decolorized with diatomaceous earth and filtered to obtain the filtrate. Potassium hydroxide solution is added to the filtrate until the pH reaches 11, and then anhydrous ethanol is added. The solution is cooled at 2℃ to crystallize and obtain the crude product. Recrystallization is then carried out for 7 hours, and solid-liquid separation is performed to obtain the filter cake. The filter cake is vacuum dried at 78℃ for 25 minutes to obtain 32.4g of potassium sucrose octasulfate with a purity of 98.8% and a yield of 92%.

[0027] Example 5:

[0028] A process for synthesizing sucrose octasulfate salt is as follows: 38g of sulfur trioxide pyridine and 23g of pyridine are heated to 39℃ and stirred at 270r / min. 13g of sucrose is added. Then, nitrogen gas is introduced and the temperature is slowly raised to 78℃, and the reaction is carried out for 7h. Pyridine is then separated through a reflux condenser. 130ml of distilled water is added to dissolve the residual solid, and the solution is decolorized with diatomaceous earth and filtered to obtain the filtrate. Potassium hydroxide solution is added to the filtrate until the pH reaches 11, and then anhydrous ethanol is added. The solution is cooled at 4℃ to crystallize and obtain the crude product. Recrystallization is then carried out for 7h, and solid-liquid separation is performed to obtain the filter cake. The filter cake is vacuum dried at 78℃ for 30min to obtain 35.4g of potassium sucrose octasulfate with a purity of 98.7% and a yield of 92%.

[0029] Example 6:

[0030] A process for synthesizing sucrose octasulfate salt is as follows: 40g of sulfur trioxide pyridine and 25g of pyridine are heated to 40℃ and stirred at 300r / min. 15g of sucrose is added. Then, nitrogen gas is introduced and the temperature is slowly raised to 80℃, and the reaction is carried out for 7h. The pyridine is then separated through a reflux condenser. 150ml of distilled water is added to dissolve the residual solid, and the solution is decolorized with diatomaceous earth and filtered to obtain the filtrate. Potassium hydroxide solution is added to the filtrate until the pH reaches 12, and then anhydrous ethanol is added. The solution is cooled at 5℃ to crystallize and obtain the crude product. Recrystallization is then carried out for 7h, and the solid and liquid are separated to obtain the filter cake. The filter cake is vacuum dried at 80℃ for 30min to obtain 37.3g of potassium sucrose octasulfate with a purity of 97.5% and a yield of 92%.

[0031] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the synthesis of sucrose octasulfate salt, characterized in that, The steps are as follows: S1. Heat 30-40g of sulfur trioxide pyridine and 15-25g of pyridine to 35-40℃, stir and mix at 200-300r / min, and add 10-15g of sucrose; S2. Then, nitrogen gas is introduced and the temperature is slowly raised to 75-80°C, and the reaction is carried out for 5-7 hours. S3. Then, pyridine is separated by reflux condenser, and 50-150 ml of distilled water is added to dissolve the residual solid. The filtrate is obtained by decolorization and filtration with diatomaceous earth. S4. Add potassium hydroxide solution to the filtrate until the pH is 9-12, then add anhydrous ethanol, and cool at 0-5°C to crystallize and obtain crude product. S5. Then recrystallize for 6-7 hours, separate the solid and liquid to obtain a filter cake, and vacuum dry the filter cake at 70℃-80℃ for 20-30 minutes to obtain the target product.

2. The process for synthesizing sucrose octasulfate salt according to claim 1, characterized in that: In step S1, 35g of sulfur trioxide pyridine and 20g of pyridine are heated to 35°C and mixed by stirring at 220r / min, and 12g of sucrose is added.

3. The process for synthesizing sucrose octasulfate salt according to claim 1, characterized in that: In step S2, nitrogen gas is then introduced and the temperature is slowly raised to 78°C, and the reaction is carried out for 6 hours.

4. The process for synthesizing sucrose octasulfate salt according to claim 1, characterized in that: In step S3, pyridine is then separated through a reflux condenser, and 100 ml of distilled water is added to dissolve the remaining solid. The filtrate is then obtained by decolorization and filtration with diatomaceous earth.

5. The process for synthesizing sucrose octasulfate salt according to claim 1, characterized in that: In step S4, potassium hydroxide solution is added to the filtrate until the pH is 9-12, then anhydrous ethanol is added, and the mixture is cooled at 0°C to crystallize and obtain the crude product.

6. The process for synthesizing sucrose octasulfate salt according to claim 5, characterized in that: Add 20% potassium hydroxide solution until the pH reaches 10.

7. The process for synthesizing sucrose octasulfate salt according to claim 1, characterized in that: In step S5, recrystallize for 6.5 hours, separate the solid and liquid to obtain a filter cake, and then vacuum dry the filter cake at 75°C for 25 minutes to obtain the target product.