A process for the preparation of sucralose and its use

Abstract

The application discloses a preparation method of sucralose and application thereof, and belongs to the technical field of fine chemical industry, and the method comprises the following steps: firstly, mixing sucrose with DMF, adding ionic liquid, and performing pretreatment under microwave irradiation; then, adding trichloroethane and thionyl chloride, and performing chlorination reaction under microwave irradiation to obtain a chlorination product liquor; cooling the chlorination product liquor, adjusting pH, and performing decomposition reaction, and then performing neutralization and concentration to obtain a sucralose tetrachloride water phase; adding an alkaline hydrolysis agent, a phase transfer catalyst and ionic liquid, and performing alkaline hydrolysis and dechlorination reaction under microwave irradiation; after the alkaline hydrolysis and dechlorination reaction is completed, adjusting pH, adding ionic liquid and butyl acetate, and performing extraction separation; and performing recrystallization purification on the obtained sucralose product. Through the synergistic effect of microwave and ionic liquid, the reaction time is remarkably shortened, the reaction selectivity and yield are improved, the purity of the sucralose product can reach 99.3%, and the total yield can reach more than 68.4%.

Description

Technical Field

[0001] This invention belongs to the technical field of fine chemicals, specifically relating to a method for preparing sucralose and its application. Background Technology

[0002] Sucralose (TGS) is one of the best-performing high-intensity sweeteners available today, with a sweetness approximately 600 times that of sucrose. It features a pure taste, no calories, good stability, and high safety, and has been widely used in beverages, food, daily chemicals, and pharmaceuticals.

[0003] Currently, the mainstream production process for sucralose is the monoesterification method, which includes three main steps: acylation protection, chlorination, and alcohol desorption protection. This process has the following prominent problems: the entire process is lengthy, requires the use of organotin catalysts, and poses a risk of heavy metal contamination; secondly, the entire process generates acetic acid as a byproduct, causing severe corrosion to equipment; and thirdly, the overall yield of the entire process is only 40%–45%.

[0004] Chinese patent CN116368145B provides an improved method that directly uses sucrose as a raw material to produce tetrachlorosucrose through a chlorination reaction, and then selectively removes the chlorine atom at the 6-position of tetrachlorosucrose through an alkaline hydrolysis reaction to obtain trichlorosucrose. Although this method eliminates the step of protecting the hydroxyl group at the 6-position of sucrose required in the traditional process, it has the following drawbacks: the chlorination reaction uses a stepped heat conduction heating (10℃~35℃~75℃~100℃, total time 4~5h), which is energy-intensive and time-consuming; the chlorinated product needs to be adjusted to alkaline conditions for decomposition reaction, resulting in a narrow operating window; the separation of tetrachlorosucrose requires 4~6 extractions with butyl acetate, resulting in high solvent consumption; and the alkaline hydrolysis uses tetramethyl / tetraethyl / tetrabutylammonium hydroxide (quaternary ammonium base), which is costly.

[0005] In addition, Chinese patent CN117210518A discloses an enzymatic method for synthesizing sucralose, which uses a dehalogenase (halogenated hydrocarbon dehalogenase EC3.8.1.5) to selectively dehalogenate the chlorinated product. The aim is to utilize the enzyme's high site selectivity and high stereoselectivity to simplify the synthesis steps, reduce energy consumption, and thus improve product yield and purity. However, the enzyme preparation used in this patent is expensive, difficult to transport and store, and its activity is easily deactivated, limiting its industrial application.

[0006] Based on this, and building upon the aforementioned publicly disclosed direct chlorination-selective dechlorination technology concept, the urgent problem to be solved is how to improve the reaction selectivity and yield of the sucralose synthesis process without involving the use of biological enzymes, through process improvement or the introduction of new technologies, to significantly shorten the reaction time and reduce process energy consumption, making it more suitable for industrial promotion and production. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing sucralose and its application to solve the problems mentioned in the background art or to achieve better technical effects.

[0008] To solve the above-mentioned technical problems, the inventors, through practice and summarization, derived the technical solution of this invention, which discloses a method for preparing sucralose, the steps of which are as follows:

[0009] S1: Mix sucrose with N,N-dimethylformamide, add ionic liquid, place in a microwave reactor, and pretreat under microwave radiation;

[0010] This step, through the introduction of ionic liquids, can disrupt the hydrogen bond network between and within sucrose molecules, allowing sucrose molecules to be more uniformly dispersed in DMF, increasing the reactivity of hydroxyl groups, and thus benefiting the regioselectivity of subsequent chlorination reactions.

[0011] S2: Trichloroethane and thionyl chloride are added to the system after S1 pretreatment, and chlorination reaction is carried out under microwave radiation to obtain chlorinated product liquid.

[0012] The mechanism of this step using microwave-assisted chlorination is as follows: the volume heating effect of microwaves causes a uniform increase in temperature within the reaction system, avoiding the temperature gradient and local overheating problems present in traditional heat conduction heating; the non-thermal effect of microwaves can lower the activation energy of the chlorination reaction and increase the reaction rate; at the same time, the selective heating of polar molecules (such as DMF and thionyl chloride) by microwaves can enhance their reactivity; through the synergistic effect of microwaves and ionic liquid pretreatment, the chlorination reaction time is significantly shortened while the selectivity of the chlorination reaction is improved, and the yield of the key intermediate sucralose is increased.

[0013] S3: Cool the chlorinated product solution obtained in S2 to 0~10℃, adjust the pH to 9~11, and carry out the decomposition reaction; then adjust the pH to 6~8, concentrate the neutralized solution to dryness, and recover DMF and trichloroethane; dissolve the residue in water to obtain a tetrachlorosucrose aqueous phase; add an alkaline hydrolysate, a phase transfer catalyst, and an ionic liquid to the tetrachlorosucrose aqueous phase, and carry out an alkaline dechlorination reaction under microwave radiation;

[0014] In this step, the added phase-transfer catalyst can transfer the inorganic base from the aqueous phase to the organic phase (the phase containing sucralose), enabling the dechlorination reaction to proceed efficiently under homogeneous or quasi-homogeneous conditions. In addition, the added ionic liquid can synergistically work with microwaves to further improve the phase-transfer catalytic efficiency, reaction rate, and selectivity. In this step, the chlorine atom at position 6 of sucralose is selectively removed to generate sucralose. By adopting the synergistic strategy of "phase-transfer catalyst + microwave assistance + ionic liquid", the efficiency and selectivity of the dechlorination reaction are significantly improved, ultimately achieving a significant increase in the total yield and purity of sucralose.

[0015] S4: After the alkaline dechlorination reaction in S3 is completed, adjust the pH of the system to 6-8 to obtain an aqueous solution of crude sucralose; concentrate the aqueous solution of crude sucralose, add ionic liquid and butyl acetate for extraction, combine the organic phases, and the aqueous phase is the raffinate containing sucralose; concentrate the organic phase to recover butyl acetate and ionic liquid; concentrate the raffinate to dryness, add methanol to dissolve, filter to remove inorganic salts, concentrate the filtrate to dryness, add water to dissolve, and obtain the initial sucralose product;

[0016] This step, by introducing ionic liquids, can change the two-phase partition coefficient of the extraction system, increase the partition ratio of sucralose / trichlorosucralose in the organic phase, thereby reducing the number of extractions and the amount of solvent used.

[0017] S5: Dissolve the sucralose primary product obtained in S4 in an ethanol-water mixed solvent, slowly cool until crystallization occurs, keep warm, filter, and dry to obtain the sucralose product.

[0018] Furthermore, in S1, the mass-to-volume ratio of sucrose to N,N-dimethylformamide is 1 g:(3~5) mL.

[0019] Further, in S1, the ionic liquid is 1-ethyl-3-methylimidazolium tetrafluoroborate; the amount of the ionic liquid is 5-20% of the sucrose mass; the microwave pretreatment power is 200-400W, the temperature is 50-70℃, and the time is 10-30min.

[0020] Furthermore, in S1, the amount of ionic liquid used is 10% of the mass of sucrose.

[0021] Furthermore, in S2, the molar ratio of sucrose to thionyl chloride is 1:6~10; and the volume ratio of thionyl chloride to trichloroethane is 1:4~5.

[0022] Furthermore, in S2, the power of the microwave radiation is 400~800W and the frequency is 2450MHz; the chlorination reaction is carried out in a closed reaction vessel, the reaction pressure is 0.3~0.8MPa, the reaction temperature is 85~110℃, and the reaction time is 0.5~1.5h.

[0023] Further, in step S3, the alkaline hydrolysant is an inorganic alkaline aqueous solution with a concentration of 10-30 wt%, wherein the inorganic alkaline is selected from any one of NaOH, KOH, and Ca(OH)2; the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, and polyethylene glycol; the amount of phase transfer catalyst added is 0.5-5% of the mass of sucralose; and the ionic liquid is [EMIM]BF4, and the amount added is 1-5% of the volume of the aqueous phase.

[0024] Furthermore, in S3, the conditions for microwave-assisted alkaline dechlorination are: microwave power 100~300W, pH=10.5~12.5, temperature 25~45℃, and reaction time 0.5~2h.

[0025] Furthermore, in S3, the added phase transfer catalyst transfers the inorganic base from the aqueous phase to the organic phase, enabling the dechlorination reaction to proceed efficiently under homogeneous or quasi-homogeneous conditions; the added ionic liquid and microwaves work synergistically to further improve the phase transfer catalytic efficiency, increase the reaction rate and selectivity, and selectively remove the chlorine atom at position 6 of sucralose to generate sucralose trichlorosaccharide.

[0026] Furthermore, the sucralose prepared by any of the above-described methods can be used in the food, daily chemical, or pharmaceutical fields.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] (1) The present invention uses microwave synergistic ionic liquid to pretreat sucrose before chlorination reaction, which can effectively destroy the intramolecular and intermolecular hydrogen bond network of sucrose molecules and improve the reactivity of its hydroxyl groups. This pretreatment step has a synergistic effect with the subsequent microwave-assisted chlorination reaction, which not only greatly shortens the chlorination reaction time from 4-5 hours in the traditional process to 0.5-1.5 hours and significantly reduces energy consumption, but more importantly, it improves the selectivity of chlorination reaction, making the content of the key intermediate sucralose more than 10% higher than that of the traditional step heating chlorination method.

[0029] (2) In the alkaline dechlorination step, this invention combines phase transfer catalyst, ionic liquid and microwave-assisted heating for the first time. The synergistic effect of the three overcomes the defects of long reaction time and poor selectivity of traditional quaternary ammonium alkaline dechlorination method. Under mild conditions (25~45℃), the dechlorination reaction can be completed efficiently within 1 hour, and the total yield of sucralose can reach more than 68.4%.

[0030] (3) In the product extraction and separation step, the present invention introduces ionic liquid as an extraction aid, which effectively changes the two-phase distribution coefficient and reduces the number of extractions of butyl acetate from 4 to 5 times in the traditional process to 2 to 3 times, greatly reducing the amount of organic solvent used. Moreover, the ionic liquid can be recycled and reused, making the process greener and more environmentally friendly, and more suitable for industrial production. Attached Figure Description

[0031] Figure 1 This is a flowchart of the sucralose preparation method of the present invention;

[0032] Figure 2 This is a photograph of the sucralose product obtained by the preparation method of Example 1 in this invention. Detailed Implementation

[0033] To make the above-mentioned objectives, 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 specific examples.

[0034] Unless otherwise specified, all raw materials or reagents used in the following examples are commercially available products.

[0035] The sucrose is commercially available food-grade or analytical grade, with a purity of ≥99.0%.

[0036] N,N-Dimethylformamide (DMF) was commercially available in analytical grade with a purity ≥99.5%.

[0037] The detection method for sucralose prepared in the following embodiments or comparative examples of the present invention is as follows:

[0038] The content and purity of sucralose were determined by high performance liquid chromatography (HPLC). The specific conditions were as follows: column: C18 column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile-water (volume ratio 70:30); flow rate: 1.0 mL / min; detection wavelength: 190 nm; column temperature: 30 ℃; injection volume: 10 μL.

[0039] The total yield of sucralose (based on sucrose) is calculated using the following formula:

[0040] Total yield of sucralose = ×100%;

[0041] Where m is the actual mass of sucralose obtained (quantified by HPLC external standard method).

[0042] M represents the theoretically obtainable mass of sucralose through complete conversion; the molecular weight of sucrose is 342.30, the molecular weight of sucralose is 397.64, and the theoretical conversion coefficient is 397.64 / 342.30≈1.162.

[0043] A method for preparing sucralose, such as Figure 1 As shown, the steps are as follows:

[0044] S1: Microwave-assisted ionic liquid pretreatment

[0045] Sucrose and N,N-dimethylformamide (DMF) were mixed at a mass-to-volume ratio of 1 g:(3~5) mL, followed by the addition of ionic liquid 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM]BF4), and the mixture was placed in a microwave reactor for pretreatment under microwave irradiation.

[0046] The amount of ionic liquid added is 5-20% of the sucrose mass;

[0047] The microwave pretreatment has a power of 200~400W, a temperature of 50~70℃, and a time of 10~30min;

[0048] This step, through the introduction of ionic liquids, can disrupt the hydrogen bond network between and within sucrose molecules, allowing sucrose molecules to be more uniformly dispersed in DMF, increasing the reactivity of hydroxyl groups, and thus benefiting the regioselectivity of subsequent chlorination reactions.

[0049] S2: Microwave-assisted chlorination reaction

[0050] Trichloroethane and thionyl chloride were added to the pretreated S1 system, and a chlorination reaction was carried out under microwave irradiation to obtain a chlorinated product liquid.

[0051] The microwave radiation has a power of 400~800W and a frequency of 2450MHz;

[0052] The chlorination reaction is carried out in a closed reaction vessel at a pressure of 0.3-0.8 MPa, a temperature of 85-110°C, and a time of 0.5-1.5 h.

[0053] The molar ratio of sucrose to thionyl chloride is 1:(6~10); the volume ratio of thionyl chloride to trichloroethane is 1:(4~5);

[0054] The mechanism of this step using microwave-assisted chlorination is as follows: the volume heating effect of microwaves causes the internal temperature of the reaction system to rise uniformly, avoiding the temperature gradient and local overheating problems existing in traditional heat conduction heating; the non-thermal effect of microwaves can reduce the activation energy of the chlorination reaction and increase the reaction rate; at the same time, the selective heating of polar molecules (such as DMF and thionyl chloride) by microwaves can enhance their reactivity; through the synergistic effect of microwave and ionic liquid pretreatment, the chlorination reaction time is significantly shortened while the selectivity of the chlorination reaction is improved, and the yield of the key intermediate sucralose is increased.

[0055] S3: Microwave-assisted phase transfer catalytic alkaline dechlorination

[0056] The chlorinated product solution obtained from S2 was cooled to 0-10℃, and the pH was adjusted to 9-11 with an inorganic base. The decomposition reaction was carried out for 0.5-1h, and then neutralized with an inorganic acid to pH=6-8. The neutralized solution was concentrated to dryness, and DMF and trichloroethane were recovered. The residue was dissolved in water to obtain a tetrachlorosucrose aqueous phase. An alkaline hydrolysis agent, a phase transfer catalyst, and an ionic liquid were added to the tetrachlorosucrose aqueous phase, and an alkaline dechlorination reaction was carried out under microwave irradiation.

[0057] The alkaline hydrolysant is an aqueous solution of an inorganic alkali (selected from NaOH, KOH, and Ca(OH)2) with a concentration of 10-30 wt%.

[0058] The phase transfer catalyst is selected from one or more of tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), tetrabutylammonium chloride and polyethylene glycol (PEG-400, PEG-600); the amount of phase transfer catalyst added is 0.5-5% of the mass of sucralose.

[0059] The ionic liquid is [EMIM]BF4, and the amount added is 1-5% of the volume of the aqueous phase;

[0060] The conditions for microwave-assisted alkaline dechlorination are: microwave power 100~300W, pH=10.5~12.5, temperature 25~45℃, and reaction time 0.5~2h;

[0061] In this step, the added phase-transfer catalyst can transfer the inorganic base from the aqueous phase to the organic phase (the phase containing sucralose), enabling the dechlorination reaction to proceed efficiently under homogeneous or quasi-homogeneous conditions. In addition, the added ionic liquid can synergistically work with microwaves to further improve the phase-transfer catalytic efficiency, reaction rate, and selectivity. In this step, the chlorine atom at position 6 of sucralose is selectively removed to generate sucralose. By adopting the synergistic strategy of "phase-transfer catalyst + microwave assistance + ionic liquid", the efficiency and selectivity of the dechlorination reaction are significantly improved, ultimately achieving a significant increase in the total yield and purity of sucralose.

[0062] S4: Ionic liquid circulating extraction and separation

[0063] After the alkaline dechlorination reaction in S3 is completed, the pH of the system is adjusted to 6-8 with hydrochloric acid to obtain an aqueous solution of crude sucralose. The aqueous solution of crude sucralose is concentrated to 1 / 3 to 1 / 2 of its original volume, and ionic liquid ([EMIM]BF4) and butyl acetate are added at a volume ratio of ionic liquid to butyl acetate of 1:(5-20) for extraction. After extraction 2-3 times, the organic phases are combined, and the aqueous phase is the raffinate containing sucralose. The organic phase is concentrated to recover butyl acetate and ionic liquid, and the ionic liquid can be recycled. The raffinate is concentrated to dryness, dissolved in methanol, filtered to remove inorganic salts, the filtrate is concentrated to dryness, dissolved in water, decolorized by activated carbon, and crystallized to obtain the primary sucralose product.

[0064] This step, by introducing ionic liquids, can change the two-phase partition coefficient of the extraction system, increase the partition ratio of sucralose / trichlorosucralose in the organic phase, thereby reducing the number of extractions and the amount of solvent used.

[0065] S5: Purification and refining of sucralose products

[0066] The sucralose precursor obtained in S4 was dissolved in an ethanol-water mixture (volume ratio 7:3-9:1) at 60-80℃, and the solution was slowly cooled to 0-10℃ to crystallize. The solution was kept at this temperature for 2-4 hours, filtered, and dried to obtain high-purity sucralose. The actual product is shown in the image. Figure 2 As shown.

[0067] According to testing and calculation, the sucralose product prepared by the method of the present invention has a purity of up to 99.3% and a total yield of up to 68.4%.

[0068] Example 1

[0069] A method for preparing sucralose, comprising the following steps:

[0070] S1: Add 200g sucrose, 800mL DMF and 20g [EMIM]BF4 (10% of the sucrose mass) to the reaction vessel in sequence, place it in a microwave reactor, set the microwave power to 300W and the temperature to 60℃, and pretreat for 20min;

[0071] S2: Add 1350 mL of trichloroethane and 300 mL of thionyl chloride (the molar ratio of sucrose to thionyl chloride is approximately 1:7.3) to the system pretreated by S1. Seal the reaction vessel, set the microwave power to 600 W, the frequency to 2450 MHz, the reaction temperature to 100 °C, the pressure to 0.5 MPa, and the reaction time to 1 h. After the reaction is completed, cool the system to 5 °C.

[0072] S3: Under stirring conditions, 20wt% NaOH aqueous solution was added dropwise to adjust the pH of the system to 10, and the reaction was kept at 5℃ for 0.5h. Then, the pH was adjusted to 7 with 35wt% hydrochloric acid, the neutralized solution was concentrated to dryness, DMF and trichloroethane were recovered, the residue was dissolved in water and the volume was adjusted to 1000mL to obtain a sucralose aqueous phase (HPLC analysis showed that the sucralose content was 178.32g / L).

[0073] Add 4g TBAB (approximately 2.2% of the mass of sucralose) and 30mL [EMIM]BF4 (3% of the volume of the aqueous phase) to the aqueous phase of sucralose. Add 25wt% NaOH aqueous solution dropwise until the pH of the system reaches 11.5. Place the system in a microwave reactor, set the microwave power to 200W, the temperature to 35℃, and the reaction time to 1h. After the reaction is complete, adjust the pH to 7 with 35wt% hydrochloric acid to obtain 1475mL of crude sucralose product aqueous solution.

[0074] S4: Concentrate the crude sucralose product aqueous solution obtained in S3 to 600 mL, add butyl acetate and [EMIM]BF4 (butyl acetate: ionic liquid volume ratio = 10:1, 600 mL of butyl acetate each time), and extract twice; combine the organic phases (recover the ionic liquid), concentrate the aqueous phase to dryness, add methanol (5 times the volume of the aqueous phase) to dissolve, filter to remove sodium chloride, concentrate the filtrate to dryness, add water to dissolve, and obtain an aqueous solution;

[0075] S5: Recrystallize the aqueous solution obtained in S4 with ethanol-water (volume ratio 8:2) to obtain the sucralose product, such as... Figure 2 As shown.

[0076] HPLC analysis showed that the sucralose content was 99.1%, and the total yield based on sucrose was 68.4%.

[0077] Example 2

[0078] A method for preparing sucralose, comprising the following steps:

[0079] S1: Add 200g sucrose, 600mL DMF and 10g [EMIM]BF4 (5% of the sucrose mass) to the reaction vessel in sequence, place it in a microwave reactor, set the microwave power to 200W, the temperature to 50℃, and pre-treat for 30min;

[0080] S2: Add 1700 mL of trichloroethane and 424 mL of thionyl chloride (the molar ratio of sucrose to thionyl chloride is approximately 1:10) to the system pretreated by S1. Seal the reaction vessel, set the microwave power to 400 W, the frequency to 2450 MHz, the reaction temperature to 85 °C, the pressure to 0.3 MPa, and the reaction time to 1.5 h. After the reaction is completed, cool the system to 0 °C.

[0081] S3: Under stirring conditions, add 20wt% KOH aqueous solution dropwise to adjust the pH of the system to 9, and keep the reaction at 0℃ for 1h; then adjust the pH to 6 with 35wt% hydrochloric acid, concentrate the neutralized solution to dryness, recover DMF and trichloroethane, dissolve the residue in water, and make up to 1000mL to obtain a sucralose aqueous phase (HPLC analysis showed that the sucralose content was 165.87g / L).

[0082] Add 1.7 g PEG-400 (approximately 1% of the mass of sucralose) and 10 mL [EMIM]BF4 (1% of the volume of the aqueous phase) to the aqueous phase of sucralose. Add 30 wt% KOH aqueous solution dropwise until the pH of the system reaches 10.5. Place the system in a microwave reactor, set the microwave power to 100 W, the temperature to 25 °C, and the reaction time to 2 h. After the reaction is complete, adjust the pH to 6 with 35 wt% hydrochloric acid to obtain 1460 mL of crude sucralose product aqueous solution.

[0083] S4: Concentrate the aqueous solution of crude sucralose obtained in S3 to 500 mL, add butyl acetate and [EMIM]BF4 (butyl acetate: ionic liquid volume ratio = 5:1, butyl acetate volume 500 mL each time), and extract 3 times; combine the organic phases (recover the ionic liquid), concentrate the aqueous phase to dryness, add methanol (4 times the volume of the aqueous phase) to dissolve, filter to remove potassium chloride, concentrate the filtrate to dryness, add water to dissolve, and obtain an aqueous solution;

[0084] S5: Recrystallize the aqueous solution obtained in S4 with ethanol-water (volume ratio 7:3) to obtain sucralose product.

[0085] HPLC analysis showed that the sucralose content was 98.8%, and the total yield based on sucrose was 65.2%.

[0086] Example 3

[0087] A method for preparing sucralose, comprising the following steps:

[0088] S1: Add 200g sucrose, 1000mL DMF and 40g [EMIM]BF4 (20% of the sucrose mass) to the reaction vessel in sequence, place it in a microwave reactor, set the microwave power to 400W and the temperature to 70℃, and pretreat for 15min;

[0089] S2: Add 1065 mL of trichloroethane and 213 mL of thionyl chloride (the molar ratio of sucrose to thionyl chloride is approximately 1:5) to the system pretreated by S1. Seal the reaction vessel, set the microwave power to 800 W, the frequency to 2450 MHz, the reaction temperature to 110 °C, the pressure to 0.8 MPa, and the reaction time to 0.5 h. After the reaction is completed, cool the system to 10 °C.

[0090] S3: Under stirring conditions, 20wt% NaOH aqueous solution was added dropwise to adjust the pH of the system to 11, and the reaction was kept at 10℃ for 0.5h. Then, the pH was adjusted to 8 with 35wt% hydrochloric acid, the neutralized solution was concentrated to dryness, DMF and trichloroethane were recovered, the residue was dissolved in water and the volume was adjusted to 1000mL to obtain a sucralose aqueous phase (HPLC analysis showed that the sucralose content was 172.54g / L).

[0091] Add 8.6 g TEBA (approximately 5% of the mass of sucralose) and 50 mL [EMIM]BF4 (5% of the volume of the aqueous phase) to the aqueous phase of sucralose. Add 25 wt% KOH aqueous solution dropwise until the pH of the system reaches 12.5. Place the system in a microwave reactor, set the microwave power to 300 W, the temperature to 45 °C, and the reaction time to 0.5 h. After the reaction is complete, adjust the pH to 8 with 35 wt% hydrochloric acid to obtain 1482 mL of crude sucralose product aqueous solution.

[0092] S4: Concentrate the aqueous solution of crude sucralose obtained in S3 to 700 mL, add butyl acetate and [EMIM]BF4 (butyl acetate: ionic liquid volume ratio = 20:1, butyl acetate volume 700 mL each time), and extract twice; combine the organic phases (recover the ionic liquid), concentrate the aqueous phase to dryness, add methanol (6 times the volume of the aqueous phase) to dissolve, filter to remove potassium chloride, concentrate the filtrate to dryness, add water to dissolve, and obtain an aqueous solution;

[0093] S5: Recrystallize the aqueous solution obtained in S4 with ethanol-water (volume ratio 9:1) to obtain sucralose product.

[0094] HPLC analysis showed that the sucralose content was 99.3%, and the total yield based on sucrose was 67.1%.

[0095] Example 4

[0096] A method for preparing sucralose, comprising the following steps:

[0097] S1: Add 200g sucrose, 800mL DMF and 20g [EMIM]BF4 (10% of the sucrose mass) to the reaction vessel in sequence, place it in a microwave reactor, set the microwave power to 300W and the temperature to 60℃, and pretreat for 20min;

[0098] S2: Add 1350 mL of trichloroethane and 300 mL of thionyl chloride (the molar ratio of sucrose to thionyl chloride is approximately 1:7.3) to the system pretreated by S1. Seal the reaction vessel, set the microwave power to 600 W, the frequency to 2450 MHz, the reaction temperature to 100 °C, the pressure to 0.5 MPa, and the reaction time to 1 h. After the reaction is completed, cool the system to 5 °C.

[0099] S3: Under stirring conditions, 20wt% NaOH aqueous solution was added dropwise to adjust the pH of the system to 10, and the reaction was kept at 5℃ for 0.5h. Then, the pH was adjusted to 7 with 35wt% hydrochloric acid, the neutralized solution was concentrated to dryness, DMF and trichloroethane were recovered, the residue was dissolved in water and the volume was adjusted to 1000mL to obtain a sucralose aqueous phase (HPLC analysis showed that the sucralose content was 178.32g / L).

[0100] Add 3.5 g of tetrabutylammonium chloride (approximately 2% of the mass of sucralose) and 30 mL of [EMIM]BF4 (3% of the volume of the aqueous phase) to the aqueous phase of sucralose. Add 25 wt% NaOH aqueous solution dropwise until the pH of the system reaches 11.5. Place the system in a microwave reactor, set the microwave power to 200 W, the temperature to 40 °C, and the reaction time to 1.5 h. After the reaction is complete, adjust the pH to 7 with 35 wt% hydrochloric acid to obtain 1475 mL of crude sucralose product aqueous solution.

[0101] S4: Concentrate the crude sucralose product aqueous solution obtained in S3 to 600 mL, add butyl acetate and [EMIM]BF4 (butyl acetate: ionic liquid volume ratio = 10:1, 600 mL of butyl acetate each time), and extract twice; combine the organic phases (recover the ionic liquid), concentrate the aqueous phase to dryness, add methanol (5 times the volume of the aqueous phase) to dissolve, filter to remove sodium chloride, concentrate the filtrate to dryness, add water to dissolve, and obtain an aqueous solution;

[0102] S5: Recrystallize the aqueous solution obtained in S4 with ethanol-water (volume ratio 8:2) to obtain sucralose product.

[0103] HPLC analysis showed that the sucralose content was 98.9%, and the total yield based on sucrose was 66.8%.

[0104] Example 5

[0105] A method for preparing sucralose, different from Example 1, does not involve ionic liquid pretreatment, but only microwave chlorination followed by phase transfer catalytic alkaline hydrolysis. The steps are as follows:

[0106] S1: 200g sucrose, 800mL DMF, 1350mL trichloroethane and 300mL thionyl chloride (molar ratio of sucrose to thionyl chloride approximately 1:7.3) were added sequentially to a reaction vessel, which was then placed in a microwave reactor. The microwave power was set to 600W, the frequency to 2450MHz, the reaction temperature to 100℃, the pressure to 0.5MPa, and the reaction time to 1h. No ionic liquid pretreatment was performed.

[0107] S2: The neutralization, concentration, and water addition steps in Example 1 and S3 are the same to obtain the sucralose aqueous phase (HPLC analysis showed that the sucralose content was 162.54 g / L).

[0108] S3~S5: Microwave-assisted phase transfer catalytic alkaline dechlorination, ionic liquid cyclic extraction separation and product purification steps are the same as in Example 1;

[0109] HPLC analysis showed that the sucralose content was 98.2%, and the total yield based on sucrose was 62.5%.

[0110] Comparative Example 1

[0111] Referring to Example 2 of Chinese Patent CN 116368145 B, the preparation method of sucralose is carried out using the traditional stepwise heating chlorination + quaternary ammonium alkaline hydrolysis method, and the steps are as follows:

[0112] S1: Dehydration step

[0113] Add 200g of sucrose and 800mL of DMF to a three-necked flask, heat to 75℃ until completely dissolved, then cool to 60℃ and evacuate to a vacuum of -0.1MPa for dehydration. Dehydration is complete when the water content in the collected DMF is 0.25wt%, yielding 663mL of sucrose solution.

[0114] S2: Traditional stepped heating chlorination

[0115] Add 1350 mL of trichloroethane to a three-necked flask, then add 300 mL of thionyl chloride dropwise, maintaining the system temperature at 0 °C. After the addition is complete, add 663 mL of sucrose solution to make up the volume. Gradually increase the temperature to 15 °C and hold for 45 min, 40 °C and hold for 45 min, 80 °C and hold for 1.75 h, and 105 °C and hold for 1.25 h (total reaction time is approximately 4.5 h). After the reaction is complete, cool the system to 5 °C.

[0116] S3: Neutralization and separation of sucralose

[0117] Add 20wt% ammonia to bring the pH to 10, react at 5℃ for 45 min, adjust the pH to 7 with 35wt% hydrochloric acid to obtain 2250 mL of chlorination neutralization solution; concentrate to dryness, recover DMF and trichloroethane, dissolve the residue in water and make up to 1000 mL to obtain sucralose aqueous phase (HPLC analysis showed sucralose content to be 161.23 g / L).

[0118] S4: Quaternary ammonium alkaline hydrolysis (without phase transfer catalyst and microwave)

[0119] The aqueous solution of sucralose was cooled to 10°C, and 25wt% tetrabutylammonium hydroxide aqueous solution was added dropwise until the pH of the system was 12.5. The temperature was controlled at 10°C and the reaction was maintained for 1 hour. After the reaction was completed, the pH was adjusted to 6 with 35wt% hydrochloric acid to obtain 1470mL of crude sucralose product aqueous solution.

[0120] S5: Separation and purification (conventional butyl acetate extraction multiple times, without the addition of ionic liquids)

[0121] The crude sucralose product aqueous solution was extracted five times with butyl acetate (the volume ratio of butyl acetate to aqueous phase was 1:1 each time). The organic phases were combined, the aqueous phase was concentrated to dryness, methanol (5 times the volume of the aqueous phase) was added to dissolve it, the solution was filtered, the filtrate was concentrated to dryness, water was added to dissolve it, and it was recrystallized with ethanol-water.

[0122] The prepared sucralose product was analyzed by HPLC and found to have a sucralose content of 97.5% and a total yield of 60.2% based on sucrose.

[0123] Comparative Example 2

[0124] A method for preparing sucralose, differing from Example 1, omits the phase transfer catalyst and ionic liquid, and uses a quaternary ammonium base for alkaline hydrolysis; the steps are as follows:

[0125] S1: Microwave-assisted chlorination reaction is the same as S2 in Example 1;

[0126] S2: Neutralization and crude separation of sucralose are the same as in S3 of Example 1. After neutralization, concentration and water addition to make up to volume, a sucralose aqueous phase is obtained (HPLC analysis shows that the sucralose content is 173.85 g / L).

[0127] S3: Traditional quaternary ammonium alkaline hydrolysis (without phase transfer catalyst, ionic liquid, or microwave treatment): The sucralose aqueous solution was cooled to 5°C, and 25 wt% tetraethylammonium hydroxide aqueous solution was added dropwise until the pH of the system reached 11.5. The temperature was controlled at 5°C, and the reaction was maintained at this temperature for 2.5 h. The remaining operations were the same as in Comparative Example 1.

[0128] The prepared sucralose product was analyzed by HPLC and found to have a sucralose content of 98.0% and a total yield of 62.8% based on sucrose.

[0129] Comparative Example 3

[0130] A method for preparing sucralose, differing from Example 1, involves only microwave chlorination followed by phase transfer catalytic alkaline hydrolysis, but without the addition of ionic liquids or microwave-assisted alkaline hydrolysis; details are as follows:

[0131] S1: Microwave-assisted chlorination reaction is the same as S2 in Example 1.

[0132] S2: Neutralization and crude separation of sucralose are the same as in S3 of Example 1. After neutralization, concentration and water addition to make up to volume, a sucralose aqueous phase is obtained (HPLC analysis shows that the sucralose content is 174.10 g / L).

[0133] S3: Phase transfer catalytic alkaline dechlorination (without ionic liquid or microwave-assisted treatment): Add 4g TBAB (approximately 2.2% of the mass of sucralose) to the aqueous phase of sucralose, add 25wt% NaOH aqueous solution dropwise until the pH of the system reaches 11.5, control the temperature at 40℃ (water bath heating), and maintain the temperature for 2 hours. The remaining operations are the same as in Example 1.

[0134] The prepared sucralose product was analyzed by HPLC and found to have a sucralose content of 97.8% and a total yield of 63.5% based on sucrose.

[0135] Comparative Example 4

[0136] A method for preparing sucralose, differing from Example 1, involves neither ionic liquid pretreatment nor ionic liquid extraction; details are as follows:

[0137] S1: Microwave-assisted chlorination reaction is the same as S1 in Example 5;

[0138] S2: Neutralization and crude separation of sucralose are the same as in S3 of Example 1. After neutralization, concentration and water addition to make up to volume, a sucralose aqueous phase is obtained (HPLC analysis shows that the sucralose content is 162.54 g / L).

[0139] S3: Microwave-assisted phase transfer catalytic alkaline dechlorination is the same as S3 in Example 1;

[0140] S4: Conventional butyl acetate extraction (without ionic liquid): Concentrate the alkaline hydrolysis product, extract it 4 times with butyl acetate (each time the volume ratio of butyl acetate to aqueous phase is 1:1), combine the organic phases, concentrate the aqueous phase to dryness, dissolve it in methanol, filter, concentrate the filtrate to dryness, dissolve it in water to obtain an aqueous solution.

[0141] S5: Product purification and refining: Same as Example 1.

[0142] The prepared sucralose product was analyzed by HPLC and found to have a sucralose content of 98.0% and a total yield of 63.1% based on sucrose.

[0143] Comparative Example 5

[0144] A method for preparing sucralose, differing from Comparative Example 1, involves only the addition of ionic liquid pretreatment; other conditions remain the same as in Comparative Example 1, as detailed below:

[0145] S1: Microwave-assisted ionic liquid pretreatment, the same as S1 in Example 1;

[0146] S2: Chlorination is carried out using a traditional stepped heating method, the same as S2 in Comparative Example 1;

[0147] S3: Neutralize and crudely separate from sucralose. Similar to S3 in Comparative Example 1, obtain sucralose aqueous phase. The sucralose content was determined to be 168.72 g / L by HPLC.

[0148] S4: Quaternary ammonium alkaline hydrolysis was used, the same as S4 in Comparative Example 1;

[0149] S5: Separation and purification, same as S5 in Comparative Example 1.

[0150] The prepared sucralose product was analyzed by HPLC and found to have a sucralose content of 97.9% and a total yield of 62.0% based on sucrose.

[0151] Comparative Example 6

[0152] A method for preparing sucralose, differing from Comparative Example 1, only adds microwave-assisted alkaline hydrolysis, while other conditions remain the same as in Comparative Example 1, as detailed below:

[0153] S1: The dehydration step is the same as S1 in Comparative Example 1;

[0154] S2: S2 in conventional stepped heating chlorination as in Comparative Example 1;

[0155] S3: Neutralize and crudely separate sucralose from S3 in Comparative Example 1 to obtain an aqueous phase containing sucralose. The sucralose content was determined to be 161.23 g / L by HPLC.

[0156] S4: Microwave-assisted quaternary ammonium alkaline hydrolysis. Sucralose aqueous solution was placed in a microwave reactor, and 25wt% tetrabutylammonium hydroxide aqueous solution was added dropwise until the pH of the system was 12.5. The microwave power was set to 200W, the temperature was controlled at 40℃, and the reaction time was 1h. The remaining operations were the same as those in Comparative Example 1.

[0157] The obtained sucralose product was analyzed by HPLC and found to contain 98.1% sucralose, with a total yield of 63.3% based on sucrose.

[0158] The preparation methods and the products obtained by comparing the above Examples 1-5 with those of Comparative Examples 1-6 are shown in Table 1 below.

[0159] Table 1. Comparison of the effects of Examples 1-5 and Comparative Examples 1-6

[0160]

[0161] The results in Table 1 above show that the microwave-assisted heating of this invention can significantly shorten the chlorination reaction time and reduce the power consumption and energy consumption of the entire reaction process; while the synergistic effect of ionic liquid pretreatment and microwave can significantly improve the selectivity of the chlorination reaction and increase the yield of sucralose intermediate.

[0162] The comparison between Example 1 and Comparative Example 1 shows that the content of sucralose intermediate in Example 1 is 178.32 g / L, while the content of sucralose intermediate in Comparative Example 1 is 161.23 g / L. This indicates that the microwave heating used in this invention not only shortens the chlorination reaction time from the original 4.5 h to 1 h (a reduction of nearly 78%), but also increases the content of sucralose intermediate by 10.6% (from 161.23 g / L to 178.32 g / L).

[0163] The comparison between Example 5 and Comparative Example 1 shows that when the entire process uses only microwave chlorination without ionic liquid pretreatment, the increase in the content of sucralose intermediate is limited (nearly 0.8%). This indicates that the accelerating effect of microwave on the chlorination reaction is mainly reflected in the reaction kinetics, while the improvement in selectivity is limited. However, when microwave and ionic liquid pretreatment are used in combination (e.g., Example 1, 178.32 g / L), the sucralose content is 10.6% higher than that in Comparative Example 1. This shows that ionic liquid pretreatment, by disrupting the hydrogen bond network of sucrose molecules and increasing the reactivity of hydroxyl groups, has a synergistic effect with microwave heating.

[0164] A comparison of Examples 1, 2, and 3 shows that Comparative Example 1, using quaternary ammonium alkali (tetrabutylammonium hydroxide) for alkaline dechlorination at 10°C for 1 hour, yielded a total yield of 60.2% for sucralose. Comparative Example 2, using microwave chlorination + quaternary ammonium alkali hydrolysis (but without phase transfer catalyst), yielded a total yield of 62.8% for sucralose. Comparative Example 3, using microwave chlorination + phase transfer catalysis (TBAB) but without ionic liquid and microwave-assisted alkaline hydrolysis, yielded a total yield of 63.5% for sucralose. Example 1 of this invention, employing a synergistic strategy of "ionic liquid pretreatment + microwave chlorination + phase transfer catalysis + microwave-assisted alkaline hydrolysis," achieved a final sucralose yield of 68.4%. A comparison between Comparative Example 1 and Comparative Example 2 shows that introducing microwave chlorination alone can increase the final product yield by 2.6 percentage points (60.2%~62.8%), mainly because microwave chlorination can increase the content of sucralose intermediates. Comparing Comparative Examples 2 and 3, it can be seen that the introduction of phase transfer catalysis (TBAB) can increase the yield by 0.7 percentage points (62.8%~63.5%), which is a very limited increase, and the reaction time is shortened from 2.5h to 2.0h, with no significant reduction in time consumption. However, comparing Example 1 and Comparative Example 3, it can be seen that the simultaneous introduction of ionic liquid and microwave-assisted alkaline hydrolysis significantly increases the yield by 4.9 percentage points (63.5%~68.4%), and the alkaline dechlorination time is shortened from 2h to 1h, greatly reducing reaction energy consumption and power consumption, and improving reaction efficiency. This is because: when phase transfer catalysis, microwave assistance, and ionic liquid are used synergistically, a significant synergistic effect is produced (an additional increase of about 4.9 percentage points); microwave-assisted heating enables the phase transfer catalytic reaction to reach a higher conversion rate in a shorter time; ionic liquid, as a microwave absorber, enhances the thermal and non-thermal effects of microwaves, and at the same time, as a phase transfer aid, it improves the two-phase mass transfer efficiency.

[0165] The comparison of Examples 1, 5, Comparative Example 1 and Comparative Example 5 shows that the sucralose content in Example 1 (with ionic liquid pretreatment) was 178.32 g / L, with a yield of 68.4%; the sucralose content in Example 5 (without ionic liquid pretreatment) was 162.54 g / L, with a yield of 62.5%; and the sucralose content in Comparative Example 5 (with ionic liquid pretreatment but using conventional heating chlorination) was 168.72 g / L, with a yield of 62.0%. A comparison of Example 5 and Comparative Example 1 shows that microwave chlorination alone (without ionic liquid pretreatment) increased the sucralose intermediate content from 161.23 g / L to 162.54 g / L, an increase of only 0.8%. A comparison of Comparative Example 1 and Comparative Example 5 shows that ionic liquid pretreatment alone (without microwave chlorination) increased the sucralose content from 161.23 g / L to 168.72 g / L, an increase of 4.6%. A comparison of Example 1 and Example 5 shows that introducing ionic liquid pretreatment on the basis of microwave chlorination increased the sucralose content from 162.54 g / L to 178.32 g / L, an increase of up to 9.7%. A comparison of Example 1 and Comparative Example 5 shows that under ionic liquid pretreatment conditions, microwave chlorination increased the sucralose intermediate content by 5.7% compared to traditional heating chlorination. This indicates that ionic liquid pretreatment and microwave chlorination each increased sucralose content by 4.6% and 0.8% respectively. However, when used in combination, the sucralose content increased by 9.7% relative to microwave chlorination alone and by 5.7% relative to ionic liquid pretreatment alone. The combined effect (from 161.23 to 178.32, an increase of 17.09 g / L) is far greater than the sum of their individual effects (4.6% + 0.8% relative increase, i.e., 7.42 + 1.29 = 8.71 g / L). This demonstrates a significant synergistic effect between ionic liquid pretreatment and microwave chlorination. After the ionic liquid disrupts the hydrogen bonds of the sucrose molecules, the bulk heating effect of microwaves on the polar ionic liquid / sucrose system becomes more significant, further improving the regioselectivity of the chlorination reaction.

[0166] In addition, in the extraction and separation process of this invention, only two ionic liquid cyclic extractions are required; while Comparative Example 1 requires five conventional butyl acetate extractions, and Comparative Example 4 requires four conventional butyl acetate extractions. This invention, through its ionic liquid cyclic extraction system, significantly reduces the amount of organic solvent used and the number of extraction operations, simplifying the separation process. In Example 1 of this invention, by introducing an ionic liquid ([EMIM]BF4) as an extraction aid, the number of butyl acetate extractions is reduced from 4-5 times to 2 times, significantly improving extraction efficiency. The ionic liquid changes the partition coefficient between the two phases, making sucralose / trichloroose more likely to partition into the organic phase, thereby reducing the number of extractions and solvent usage. Simultaneously, the ionic liquid can be recycled, reducing the overall process cost and environmental burden.

Claims

1. A method for preparing sucralose, characterized in that, The steps are as follows: S1: Mix sucrose with N,N-dimethylformamide, add ionic liquid, place in a microwave reactor, and pretreat under microwave radiation; S2: Trichloroethane and thionyl chloride are added to the system after S1 pretreatment, and chlorination reaction is carried out under microwave radiation to obtain chlorinated product liquid. S3: Cool the chlorinated product solution obtained in S2 to 0~10℃, adjust the pH to 9~11, and carry out the decomposition reaction; then adjust the pH to 6~8, concentrate the neutralized solution to dryness, and recover DMF and trichloroethane; dissolve the residue in water to obtain a tetrachlorosucrose aqueous phase; add an alkaline hydrolysate, a phase transfer catalyst, and an ionic liquid to the tetrachlorosucrose aqueous phase, and carry out an alkaline dechlorination reaction under microwave radiation; S4: After the alkaline dechlorination reaction in S3 is completed, adjust the pH of the system to 6-8 to obtain an aqueous solution of crude sucralose; concentrate the aqueous solution of crude sucralose, add ionic liquid and butyl acetate for extraction, combine the organic phases, and the aqueous phase is the raffinate containing sucralose; concentrate the organic phase to recover butyl acetate and ionic liquid; concentrate the raffinate to dryness, add methanol to dissolve, filter to remove inorganic salts, concentrate the filtrate to dryness to obtain primary sucralose; S5: Dissolve the sucralose primary product obtained in S4 in an ethanol-water mixed solvent, slowly cool until crystallization occurs, keep warm, filter, and dry to obtain the sucralose product.

2. The method for preparing sucralose according to claim 1, characterized in that, In S1, the mass-to-volume ratio of sucrose to N,N-dimethylformamide is 1 g:(3~5) mL.

3. The method for preparing sucralose according to claim 1, characterized in that, In step S1, the ionic liquid is 1-ethyl-3-methylimidazolium tetrafluoroborate; the amount of the ionic liquid is 5-20% of the sucrose mass; the microwave pretreatment power is 200-400W, the temperature is 50-70℃, and the time is 10-30min.

4. The method for preparing sucralose according to claim 3, characterized in that, In S1, the amount of ionic liquid used is 10% of the mass of sucrose.

5. The method for preparing sucralose according to claim 1, characterized in that, In S2, the molar ratio of sucrose to thionyl chloride is 1:6~10; the volume ratio of thionyl chloride to trichloroethane is 1:4~5.

6. The method for preparing sucralose according to claim 1, characterized in that, In S2, the power of microwave radiation is 400~800W and the frequency is 2450MHz; the chlorination reaction is carried out in a closed reaction vessel, the reaction pressure is 0.3~0.8MPa, the reaction temperature is 85~110℃, and the reaction time is 0.5~1.5h.

7. The method for preparing sucralose according to claim 1, characterized in that, In step S3, the alkaline hydrolysant is an inorganic alkaline aqueous solution with a concentration of 10-30 wt%, wherein the inorganic alkaline is selected from any one of NaOH, KOH, and Ca(OH)2; the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, and polyethylene glycol; the amount of phase transfer catalyst added is 0.5-5% of the mass of sucralose; and the ionic liquid is [EMIM]BF4, and the amount added is 1-5% of the volume of the aqueous phase.

8. The method for preparing sucralose according to claim 1, characterized in that, In S3, the conditions for microwave-assisted alkaline dechlorination are: microwave power 100~300W, pH=10.5~12.5, temperature 25~45℃, and reaction time 0.5~2h.

9. The method for preparing sucralose according to claim 1, characterized in that, In S3, the added phase transfer catalyst transfers the inorganic base from the aqueous phase to the organic phase, enabling the dechlorination reaction to proceed efficiently under homogeneous or quasi-homogeneous conditions. The added ionic liquid and microwaves work synergistically to further improve the phase transfer catalytic efficiency, increase the reaction rate and selectivity, and selectively remove the chlorine atom at position 6 of sucralose to generate sucralose trichlorosucrose.

10. The application of sucralose prepared by any one of the methods described in claims 1 to 9 in the food, daily chemical, or pharmaceutical fields.

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