Purification method of sucralose-6-ester
By combining a ternary composite solvent and a mesoporous silica adsorbent with a programmed cooling crystallization method, the problem of balancing purity and yield in the purification of sucralose-6-ester was solved, achieving efficient and economical purification of sucralose-6-ester, which is suitable for industrial production.
Patent Information
- Application Number
- CN202511833682.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-08
- Publication Date
- 2026-01-23
AI Technical Summary
Existing purification methods for sucralose-6-ester cannot achieve an ideal balance between product purity, process yield, operating costs, and industrial feasibility. Traditional recrystallization methods are inefficient, organic solvent extraction methods are prone to emulsification, and column chromatography methods are costly and not suitable for large-scale production.
A programmed cooling crystallization method combining ternary composite solvent dissolution and mesoporous silica adsorbent was adopted. Through programmed cooling crystallization combining slow and rapid cooling, combined with size-selective adsorption of mesoporous silica, key impurities were removed, and efficient purification of sucralose-6-ester was achieved through stable solvent recycling.
It significantly improves product purity and yield, reduces solvent consumption and processing costs, and enhances filtration and washing efficiency, demonstrating potential for industrial application.
Smart Images
Figure CN121378360A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of sucralose-6-ester purification technology, and more specifically, to a method for purifying sucralose-6-ester. Background Technology
[0002] Sucralose, a high-intensity, non-nutritive sweetener synthesized from sucrose, is widely used in the global food and beverage industry due to its outstanding advantages such as high sweetness, pure flavor, good stability, and high safety. Sucralose-6-ester is a key intermediate in its synthesis process, and the purity of this intermediate directly determines the yield, quality, and production cost of the final product, sucralose. Therefore, developing an efficient and economical purification process for sucralose-6-ester is crucial for the development of the entire sucralose industry.
[0003] Currently, the purification of sucralose-6-ester in industry and literature mainly involves the following technical approaches, but all of them have obvious limitations: 1. Traditional recrystallization method: This method usually uses a single organic solvent or a simple binary solvent system for recrystallization. However, since sucralose-6-ester and its structural analogs, especially sucralose-4,6-diester, are very similar in physicochemical properties, traditional solvent systems are difficult to achieve efficient selective separation. This results in limited improvement in product purity, and often requires multiple recrystallizations to meet the requirements, leading to a long process flow, high solvent consumption, significantly reduced product yield, and poor economic efficiency. 2. Organic solvent extraction method: This method uses the difference in partition coefficients between the target product and impurities in different solvents for separation. Although it has a certain separation effect, in actual operation, especially in complex systems containing surface-active components, emulsification is very likely to occur, which leads to phase separation difficulties, product entrainment loss, and unstable yield. At the same time, this method is not effective in separating impurities with very similar polarities and there is a risk of organic solvent residue. 3. Column chromatography: Although column chromatography using silica gel and other packing materials can obtain products with high purity, it has low throughput, is cumbersome to operate, and is time-consuming. In addition, the cost of the chromatography packing materials and a large amount of elution solvent is high. These inherent defects make this method completely unsuitable for large-scale industrial continuous production. It is limited to laboratory-scale micro-preparation and does not have economic value for industrialization.
[0004] In summary, existing methods for purifying sucralose-6-ester cannot achieve an ideal balance between product purity, process yield, operating cost, and industrial feasibility. Therefore, this invention addresses these shortcomings by providing a method for purifying sucralose-6-ester. Summary of the Invention
[0005] In order to overcome the above-mentioned defects of the prior art, the present invention provides a method for purifying sucralose-6-ester to solve the problems mentioned in the background art.
[0006] To achieve the above objectives, the present invention provides the following technical solution: a method for purifying sucralose-6-ester, comprising the following steps: S1. Crude product dissolution and adsorption purification: Crude sucralose-6-ester is dissolved in a ternary composite solvent at 40℃ to 60℃ to form a saturated or near-saturated solution. Then, 1% to 3% of the mass of the crude product is added to the solution as mesoporous silica adsorbent, and the mixture is stirred at 40℃ to 50℃ for 20 min to 40 min for adsorption treatment. Then, the solution is hot filtered to separate and obtain the purified filtrate. S2. Programmed cooling crystallization: The purified filtrate obtained in step S1 is subjected to programmed cooling crystallization. The programmed cooling crystallization process includes at least a slow cooling crystal growth stage with a cooling rate of no more than 0.5℃ / min and a rapid cooling crystal precipitation stage with a cooling rate of no less than 0.8℃ / min. Finally, the filtrate is aged at 5℃ to 10℃ for 2h to 4h to precipitate crystals. S3. Separation and drying: The crystal slurry obtained in step S2 is subjected to solid-liquid separation. The filter cake is washed with a poor solvent pre-cooled to 0°C to 5°C. Then, it is dried under vacuum conditions of 40°C to 50°C and -0.08MPa to -0.10MPa for 4 to 6 hours to obtain high-purity sucralose-6-ester crystals.
[0007] Preferably, the ternary composite solvent in step S1 consists of a main solvent, a co-solvent, and a poor solvent. The main solvent is isopropyl acetate, the co-solvent is acetone, and the poor solvent is selected from C6-C8 straight-chain or branched alkanes. The volume ratio of the main solvent, co-solvent, and poor solvent is 3-5:1-2:0.5-1.
[0008] Preferably, the undesirable solvent is n-heptane or n-hexane, and the mass-to-volume ratio of the ternary composite solvent to the crude sucralose-6-ester is 1 g:(4 mL-8 mL).
[0009] Preferably, the mesoporous silica adsorbent in step S1 has an average pore size of 2 nm to 10 nm and a specific surface area of 300 m². 2 / g to 1000m 2 / g, wherein the mesoporous silica is of type MCM-41, SBA-15 or KIT-1, and the mesoporous silica adsorbent is vacuum activated at 100°C to 120°C for 1 to 2 hours before use.
[0010] Preferably, the programmed cooling crystallization in step S2 specifically includes the following stages performed sequentially: The first stage involves slow cooling and crystal nucleation induction: the temperature is uniformly reduced from 50℃ to 35℃ at a cooling rate of 0.3℃ / min to 0.5℃ / min. The second stage, isothermal crystal growth: maintain a constant temperature of 35℃ for 30 to 60 minutes; The third stage, rapid cooling and crystal growth: cooling from 35℃ to 10℃ at a cooling rate of 0.8℃ / min to 1.2℃ / min; The fourth stage is low-temperature aging: let it stand at 5℃ to 10℃ for 2 to 4 hours.
[0011] Preferably, at the beginning of the first stage, or when the temperature of the purified filtrate drops to 45°C to 48°C, 0.01% to 0.05% by mass of the crude product of pure sucralose-6-ester seed crystals are added to it.
[0012] Preferably, in the first and / or second stage, the stirring rate is controlled at 80 rpm to 120 rpm, and in the third and fourth stages, the stirring rate is controlled at 150 rpm to 250 rpm.
[0013] Preferably, the undesirable solvent used for pre-cooling in step S3 is n-heptane or n-hexane, the amount of washing solvent is 0.5 to 1 times the mass of the filter cake, and the drying is carried out in a vacuum rake dryer or a vacuum double cone dryer.
[0014] Preferably, the mother liquor obtained after separation in step S3 is concentrated and recovered and then returned to step S1 as part of the ternary composite solvent for recycling.
[0015] Preferably, the HPLC purity of the sucralose-6-ester crystals obtained by the method is not less than 99.5%, the yield is not less than 90%, and the content of the key impurity sucralose-4,6-diester is less than 0.1%.
[0016] The technical effects and advantages of this invention are as follows: 1. This invention utilizes the synergistic effect of ternary composite solvent, selective adsorption and programmed crystallization, and takes advantage of the synergistic effect of the solubility of each component and the size-selective adsorption of mesoporous silica to remove key impurities in advance. By controlling crystal nucleation and growth through programmed cooling, the purity of the product is significantly improved while ensuring a high yield, effectively solving the technical problem of balancing purity and yield. 2. This invention removes impurities that affect crystal form by introducing mesoporous silica for adsorption and purification before crystallization. It also adopts a multi-stage programmed cooling crystallization strategy that includes slow induction, constant temperature crystal growth, rapid growth and low temperature aging to synergistically control the nucleation and growth kinetics of crystals. This results in regular rod-shaped crystals, improves the physical properties of the product, significantly improves filtration and washing efficiency, and provides high-quality raw materials for the subsequent deesterification process. 3. By setting up a stable and recyclable solvent system and optimizing the entire process conditions, the mother liquor can be directly reused after simple concentration during the production process, and the purification effect is stable. This significantly reduces solvent consumption and waste treatment costs. At the same time, all unit operations are based on conventional equipment and the conditions are mild, which has excellent process economy, environmental protection and industrial application potential. Attached Figure Description
[0017] Figure 1 This is a flowchart illustrating the overall process flow of the present invention. Detailed Implementation
[0018] Example 1 This invention provides a method for purifying sucralose-6-ester, which requires the following raw materials and equipment: Crude sucralose-6-ester: HPLC purity 92.3%; Reagents: Isopropyl acetate, acetone, n-heptane, mesoporous silica, MCM-41 type, average pore size 4 nm, specific surface area -800 m² / g. 2 / g; Equipment: Jacketed glass reactor, precision thermostat, vacuum drying oven, HPLC and stirring control system.
[0019] Specifically, it includes the following steps: S1. Crude product dissolution and adsorption purification In a 500 mL jacketed reactor, add 20.0 g of crude sucralose-6-ester, and add a ternary composite solvent consisting of 100 mL isopropyl acetate, 30 mL acetone and 16 mL n-heptane in a volume ratio of approximately 5:1.5:0.8. Start the stirring at 200 rpm and heat to 50 °C to completely dissolve the crude product and form a near-saturated solution. Add 2% of crude MCM-41 mesoporous silica adsorbent, which has been vacuum activated at 120℃ for 1.5h, to the solution. Maintain 50℃ and stirring speed of 200rpm for 30min of adsorption treatment. Then, perform hot filtration through a preheated Buchner funnel to separate and collect the purified filtrate. S2, Programmed cooling crystallization The purified filtrate obtained in step S1 was transferred to a temperature-programmed crystallizer. Stirring was started. In the first stage, the temperature was slowly reduced from 50°C to 35°C at a rate of 0.4°C / min. When the temperature dropped to 47°C, 0.005% of the crude sucralose-6-ester pure seed crystals were added. In the second stage, after reaching 35°C, the temperature was kept constant for 45 min. The stirring rate was controlled at 100 rpm during this stage. In the third stage, the temperature was rapidly reduced from 35°C to 10°C at a rate of 1°C / min, and the stirring rate was increased to 200 rpm. In the fourth stage, the crystals were aged at 10°C for 3 hours to allow the crystals to fully separate. S3. Separation and Drying The crystal slurry from step S2 was separated by vacuum filtration to obtain wet crystals. The filter cake was washed twice with 20 mL of n-heptane pre-cooled to about 5°C (approximately 0.7 times the mass of the filter cake). The wet crystals were then transferred to a vacuum drying oven and dried at 45°C and -0.09 MPa for 5 hours to obtain white, regular rod-shaped crystals. The crystals were weighed and the yield was calculated. Samples were taken for HPLC analysis.
[0020] The mother liquor obtained from step S3 in Example 1 was collected and concentrated under reduced pressure at 50°C and -0.085 MPa to recover approximately 110 mL of mixed solvent. This recovered solvent was then replenished with a small amount of fresh solvent to the initial ratio (isopropyl acetate: acetone: n-heptane = 5:1.5:0.8) and used for the purification of the next batch of 20 g crude product. The steps were the same as in Example 1. The purity and yield of the product during recycling were recorded.
[0021] Example 2: Changing the solvent ratio This embodiment is basically the same as Example 1, but the difference is that the volume ratio of the ternary composite solvent is changed to isopropyl acetate: acetone: n-heptane = 4:1:0.6, and the total amount of solvent is adjusted proportionally to ensure that the crude product is completely dissolved.
[0022] Example 3: Changing the amount of adsorbent This embodiment is basically the same as Embodiment 1, except that the amount of mesoporous silica adsorbent added is 1% of the crude mass.
[0023] Example 4: Changing the cooling program This embodiment is basically the same as Embodiment 1, but the difference is that the rate of the first stage of programmed cooling crystallization is adjusted to 0.5℃ / min, and the rate of the third stage is adjusted to 0.8℃ / min.
[0024] Example 5, Seed Crystal Omission This embodiment is basically the same as Embodiment 1, but the difference is that no seed crystals are added in the first stage of programmed cooling crystallization.
[0025] Example 6: Mother liquor circulation In this embodiment, the mother liquor obtained in Example 1 is concentrated under reduced pressure to recover the solvent. The recovered solvent is then replenished with fresh solvent to the initial ratio (5:1.5:0.8) for the purification of the next batch of 20g of the same crude product. The operation steps are the same as in Example 1.
[0026] Comparative Example 1: Recrystallization using a traditional binary solvent, the specific steps of which are as follows: Weigh 20g of the crude product from the same batch, dissolve it in 120mL of a binary solvent of ethyl acetate / n-heptane (volume ratio 4:1), dissolve at 50℃ without adsorption treatment, cool directly to room temperature, and then place in a 0℃ ice-water bath to cool for 2h. Filter, wash, and dry.
[0027] Comparative Example 2, adsorption-free purification steps, specifically including: Except for omitting the mesoporous silica adsorption step in Example 1 (i.e., directly performing hot filtration after dissolving the crude product), the other steps are exactly the same as in Example 1.
[0028] Comparative Example 3: No programmed cooling, but rapid cooling, specifically including: Step S1 is exactly the same as in Example 1. After obtaining the purified filtrate, instead of performing programmed cooling, it is directly and rapidly placed from 50°C into a 10°C water bath and stirred for 3 hours. The remaining steps are the same as in Example 1.
[0029] Experimental test: The performance of the products from the above embodiments and comparative examples was tested, as follows: 1. HPLC purity and impurity analysis: A C18 column was used with acetonitrile / water (55:45) as the mobile phase at a flow rate of 1.0 mL / min and a UV detector of 215 nm. The purity of the main component and the content of the key impurity sucralose-4,6-diester were calculated by the area normalization method.
[0030] 2. Yield calculation: Yield (%) = (mass of purified crystals × concentration of purified product) / (mass of crude feed × concentration of crude feed) × 100%.
[0031] 3. Crystal morphology observation: The crystal morphology of the product is observed using a scanning electron microscope.
[0032] The experimental test table is as follows: Table 1: Comparison of purification effects between the examples and comparative products
[0033] result: The data in the table above shows that: 1. As can be seen from the data of Examples 1 to 6, excellent results with HPLC purity higher than 99.5%, key impurity content lower than 0.15%, and yield higher than 90% can be obtained. This fully demonstrates the reliability and wide operating window of the technical solution of the present invention. In particular, in Example 6, the effect remained stable after the mother liquor was recycled, which reflects the economy and environmental protection of the method and has outstanding industrial application value. 2. The purity and yield of Comparative Example 1 were significantly lower than those of all embodiments of the present invention, proving that the specific ternary composite solvent system is crucial for achieving high purity and high yield, and its effect is unmatched by traditional solvents. The purity of Comparative Example 2 decreased significantly, and the product color was slightly yellow, proving that the adsorption purification of mesoporous silica is a key and indispensable step in removing colored impurities and specific polar impurities. Comparative Example 3 performed the worst in terms of product purity, yield, and crystal physical morphology, strongly demonstrating the decisive role of programmed cooling crystallization in controlling crystal nucleation and growth and ensuring the overall quality of the product. Its low yield was mainly due to the loss caused by encapsulation in the mother liquor. 3. By leveraging the synergistic effect of the ternary composite solvent system, mesoporous silica adsorption purification, and programmed cooling crystallization, the long-standing technical problems of difficulty in balancing purity and yield, poor product physical properties, and high production costs in the prior art have been successfully solved. The overall effect of all embodiments is far superior to that of the comparative examples, achieving unexpected and excellent technical results, such as a significant increase in both purity and yield, regularization of crystal morphology, and improvement in filtration and washing efficiency, fully demonstrating the significant progress of this invention.
[0034] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. 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 method for purifying sucralose-6-ester, characterized in that: Includes the following steps: S1. Crude product dissolution and adsorption purification: Crude sucralose-6-ester is dissolved in a ternary composite solvent at 40℃ to 60℃ to form a saturated or near-saturated solution. Then, 1% to 3% of mesoporous silica adsorbent by mass of crude product is added to the solution, and the mixture is stirred at 40℃ to 50℃ for 20 min to 40 min for adsorption treatment. Then, the solution is hot filtered to separate and obtain the purified filtrate. S2. Programmed cooling crystallization: The purified filtrate obtained in step S1 is subjected to programmed cooling crystallization. The programmed cooling crystallization process includes at least a slow cooling crystal growth stage with a cooling rate of no more than 0.5℃ / min and a rapid cooling crystal precipitation stage with a cooling rate of no less than 0.8℃ / min. Finally, the filtrate is aged at 5℃ to 10℃ for 2h to 4h to precipitate crystals. S3. Separation and drying: The crystal slurry obtained in step S2 is subjected to solid-liquid separation. The filter cake is washed with a poor solvent pre-cooled to 0°C to 5°C. Then, it is dried under vacuum conditions of 40°C to 50°C and -0.08MPa to -0.10MPa for 4 to 6 hours to obtain high-purity sucralose-6-ester crystals.
2. The method according to claim 1, characterized in that: The ternary composite solvent in step S1 consists of a main solvent, a co-solvent, and a poor solvent. The main solvent is isopropyl acetate, the co-solvent is acetone, and the poor solvent is selected from C6-C8 straight-chain or branched alkanes. The volume ratio of the main solvent, co-solvent, and poor solvent is 3-5:1-2:0.5-1.
3. The method according to claim 2, characterized in that: The undesirable solvent is n-heptane or n-hexane, and the mass-volume ratio of the ternary composite solvent to the crude sucralose-6-ester is 1 g: (4 mL-8 mL).
4. The method according to claim 1, characterized in that: The mesoporous silica adsorbent in step S1 has an average pore size of 2 nm to 10 nm and a specific surface area of 300 m². 2 / g to 1000m 2 / g, wherein the mesoporous silica is of type MCM-41, SBA-15 or KIT-1, and the mesoporous silica adsorbent is vacuum activated at 100°C to 120°C for 1 to 2 hours before use.
5. The method according to claim 1, characterized in that: The programmed cooling crystallization in step S2 specifically includes the following stages performed sequentially: The first stage involves slow cooling and crystal nucleation induction: the temperature is uniformly reduced from 50℃ to 35℃ at a cooling rate of 0.3℃ / min to 0.5℃ / min. The second stage, isothermal crystal growth: maintain a constant temperature of 35℃ for 30 to 60 minutes; The third stage, rapid cooling and crystal growth: cooling from 35℃ to 10℃ at a cooling rate of 0.8℃ / min to 1.2℃ / min; The fourth stage is low-temperature aging: let it stand at 5℃ to 10℃ for 2 to 4 hours.
6. The method according to claim 5, characterized in that: At the beginning of the first stage, or when the temperature of the purified filtrate drops to 45°C to 48°C, add 0.01% to 0.05% of pure sucralose-6-ester seed crystals by mass of the crude product.
7. The method according to claim 5, characterized in that: In the first and / or second stage, the stirring rate is controlled at 80 rpm to 120 rpm, and in the third and fourth stages, the stirring rate is controlled at 150 rpm to 250 rpm.
8. The method according to claim 1, characterized in that: In step S3, the undesirable solvent used for pre-cooling is n-heptane or n-hexane, and the amount of washing solvent used is 0.5 to 1 times the mass of the filter cake. The drying is carried out in a vacuum rake dryer or a vacuum double cone dryer.
9. The method according to claim 1, characterized in that: The mother liquor obtained after separation in step S3 is concentrated and recovered and returned to step S1 as part of the ternary composite solvent for recycling.
10. The method according to claim 1, characterized in that: The final HPLC purity of the sucralose-6-ester crystals obtained by the method is not less than 99.5%, the yield is not less than 90%, and the content of the key impurity sucralose-4,6-diester is less than 0.1%.