A chlorination process for sucrose-6-acetate

Abstract

The application discloses a chlorination process of sucrose-6-acetate, which comprises the following steps: preparing a Vilsmeier reagent by using DMF and chlorosulfuric acid under low-temperature conditions, releasing sulfur dioxide by heating, mixing the Vilsmeier reagent with 1,1,2-trichloroethane as a reaction raw material liquid, mixing the reaction raw material liquid with a pre-cooled DMF solution of sucrose-6-acetate through a pipeline mixer, performing high-temperature chlorination reaction and removing hydrogen chloride by using a three-stage continuous reactor, and sequentially neutralizing the chlorination liquid by using ammonia water and sulfuric acid, so that the target product can be obtained by controlling pH=7-7.5. The process flow is simple, the continuous process of low-temperature mixing, high-temperature reaction and neutralization reaction is realized, the complicated process of separating hydrogen chloride and sulfur dioxide can be omitted, the product yield is improved, the number of production equipment is reduced, the production cost is lowered, and the process has good industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a chlorination method for sucrose-6-acetic acid ester. Background Technology

[0002] The selective chlorination process of sucrose-6-acetate involves multiple steps, including low-temperature dropwise addition, a three-stage heating reaction, and low-temperature neutralization. Currently, the yield of selective chlorination of sucrose-6-acetate is around 59-60%, while the yields of sucrose esterification and sucralose-6-acetate alcoholysis are both 85-95%. Therefore, selective chlorination is a key step in improving the final yield of sucralose synthesis. Currently, the chlorination process of sucrose-6-acetate is mostly carried out in batch reactors, resulting in a long reaction time (more than 10 hours), high labor intensity, difficulty in controlling reaction conditions, and easy fluctuations in process parameters due to human factors. Furthermore, due to the numerous byproducts and the difficulty in separating intermediate products, selective chlorination is also the most complex and difficult step to control. Therefore, the selective chlorination reaction of sucrose-6-acetate is currently one of the key focuses of sucralose technology and has received extensive research both domestically and internationally.

[0003] In the selective chlorination of sucrose-6-acetate, two classes of substances can be used to prepare Vilsmeier-type chlorination reagents. One class is phosphorus reagents, which produce difficult-to-separate dark-colored byproducts during the chlorination reaction, resulting in low yields. The other class is acyl chlorides, including carbonyl chlorides and sulfuryl chlorides. Since they only produce gaseous CO2 or SO2, these reagents are generally preferred for preparing Vilsmeier-type chlorination reagents for the selective chlorination of sucrose-6-acetate.

[0004] In recent years, researchers have supplemented and improved the DMF-Vilsmeier reagent system. In 1983, US4380476 disclosed a method for the first preparation of Vilsmeier reagent as a chlorination reagent for the selective chlorination of sucrose-6-acetate. Subsequently, patent US 4980463 improved upon the original method by adding a sucrose-6-acetate DMF solution to the chlorination reagent. It was found that the reverse order of addition not only avoided the formation of a difficult-to-stir solid but also improved the reaction yield. Simultaneously, a gradual increase in temperature was used to sequentially produce monochloro, dichloro, and trichlorosucrose-6-acetate, thereby reducing carbonization and impurity formation.

[0005] Furthermore, the hydrogen chloride and sulfur dioxide tail gases generated during the traditional sucralose chlorination process require complex treatment to separate them into byproducts, thereby reducing waste. Patent CN115849308A reports that the sucralose chlorination tail gas is sequentially washed through a primary, secondary, and tertiary water washing tower to absorb hydrogen chloride and produce hydrochloric acid as a byproduct. Unabsorbed tail gas enters a sulfuric acid drying tower to remove moisture. The dried tail gas is then pressurized by a compressor and passed through a primary and secondary distillation tower to obtain sulfur dioxide as the final product. Patent CN 113646062A utilizes ionic liquid adsorption combined with condensation and distillation to effectively treat the chlorination tail gas in the sucralose production process, achieving effective separation of HCl and SO2 gases to obtain high-quality hydrochloric acid and liquid SO2 products. Patent CN112221310A reports that high-temperature chlorination tail gas undergoes a process involving a secondary absorption tower, drying, compression, distillation, and absorption to obtain sulfur dioxide and hydrochloric acid products. Patent CN 107188133A discloses an apparatus and method for separating sucralose tail gas, which yields sulfur dioxide and hydrogen chloride products after drying, compression, solvent removal distillation, and refining distillation. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a method for the selective chlorination of sucrose-6-acetate using Vilsmeier's reagent. The method involves first preparing Vilsmeier's reagent using DMF and thionyl chloride, then removing sulfur dioxide through heat treatment before mixing the Vilsmeier's reagent with trichloroethane for chlorination. This avoids side reactions caused by SOCl2, improves reaction selectivity, and generates more of the target product within the same process time, resulting in a significantly higher final yield.

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

[0008] A method for chlorinating sucrose-6-acetate includes the following steps:

[0009] (1) DMF and thionyl chloride were introduced into the Vilsmeier reagent preparation vessel for mixing and the temperature was raised to 45~55℃ to remove sulfur dioxide. Then the obtained Vilsmeier reagent was mixed with 1,1,2-trichloroethane and cooled to -10~5℃ to obtain the reaction raw material solution.

[0010] (2) The reaction raw material solution obtained in step (1) and the DMF solution of sucrose-6-acetate are simultaneously introduced into the pipeline mixer for mixing. After the mixture is uniform, it is sent to a three-stage continuous reactor for high-temperature chlorination reaction and removal of the by-product hydrogen chloride.

[0011] (3) The chlorinated liquid after the high-temperature chlorination reaction is fed into the ripening reactor for a second reaction to ensure complete chlorination and further remove hydrogen chloride. The chlorinated reaction liquid is then cooled to 0~20℃ by a cooler.

[0012] (4) The chlorination reaction solution cooled in step (3) is sent to the first-stage neutralization reactor, and the pH of the neutralized material is adjusted to 8~10 using ammonia solution.

[0013] (5) The material after neutralization in step (4) is fed into the neutralization cooler. After cooling to 0~20℃, it is sent to the secondary neutralization reactor. The pH is adjusted to 7~7.5 using sulfuric acid solution to obtain the target product.

[0014] Furthermore, the molar ratio of DMF to thionyl chloride used in step (1) is 1~1.5:1.

[0015] Furthermore, the mass ratio of Vilsmeier reagent to 1,1,2-trichloroethane used in step (1) is 1:1.

[0016] Further, the feed volume flow ratio of the reaction raw material liquid and the DMF solution of sucrose-6-acetate used in step (2) is 5~10:1, and the mass concentration of sucrose-6-acetate in the DMF solution of sucrose-6-acetate is 20~45%.

[0017] Furthermore, the DMF and reaction raw material liquid used in step (2) need to be pre-cooled to -10~5℃.

[0018] Furthermore, the three-stage continuous reactor described in step (2) is composed of one or a combination of three of the following: tubular reactor, batch reactor, oscillating flow reactor, or microchannel reactor.

[0019] Furthermore, in step (2), when the high-temperature chlorination reaction is carried out, the temperatures of each reactor in the three-stage continuous reactor are 75~85℃, 90~100℃, and 105~115℃ respectively, and the residence times of each reactor are 20~120min, 20~90min, and 20~90min respectively.

[0020] Further, the maturation reactor mentioned in step (3) is one of a tubular reactor, a batch reactor, an oscillating flow reactor or a microchannel reactor, with a set temperature of 105~115℃ and a residence time of chlorinated liquid in it of 20~120min.

[0021] Further, the primary neutralization reactor in step (4) is one of a tubular reactor, an oscillating flow reactor, or a microchannel reactor; the residence time of the chlorination reaction solution in the primary neutralization reactor is 5-60 min; and the mass concentration of the ammonia solution used is 20-25%.

[0022] Further, the secondary neutralization reactor mentioned in step (5) is one of a tubular reactor, an oscillating flow reactor or a microchannel reactor; the residence time of the material in the secondary neutralization reactor is 5 to 45 minutes; and the mass concentration of the sulfuric acid solution used is 40 to 50%.

[0023] The significant advantages of this invention are:

[0024] (1) This invention proposes for the first time to prepare Vilsmeier reagent with DMF and thionyl chloride, remove sulfur dioxide by heating, and then mix it with trichloroethane for chlorination to remove hydrogen chloride. This avoids the generation of mixed gas of sulfur dioxide and hydrogen chloride in the traditional production process, realizes the separate separation of sulfur dioxide and hydrogen chloride, reduces the need for separation equipment for sulfur dioxide and hydrogen chloride, reduces production costs, avoids side reactions caused by the addition of SOCl2 in the traditional production process, improves the selectivity of the reaction, and can generate more target products in the same process time, so that the final yield is greatly increased from 59% to 71%.

[0025] (2) The present invention changes the existing intermittent production to continuous production, which can realize automated control, reduce human interference and manual operation intensity, improve equipment production efficiency, increase production output, and reduce equipment investment.

[0026] (3) By combining the pre-prepared Vilsmeier reagent with continuous chlorination reaction technology, this invention not only overcomes the complex process of separating hydrogen chloride and sulfur dioxide, but also improves product yield, reduces the number of production equipment, and lowers production costs. Therefore, this technology has great industrial application value. Detailed Implementation

[0027] A method for chlorinating sucrose-6-acetate includes the following steps:

[0028] (1) DMF pre-cooled to -10~5℃ and thionyl chloride were introduced into the Vilsmeier reagent preparation vessel at a molar ratio of 1~1.5:1 and mixed. The temperature was raised to 45~55℃ to remove sulfur dioxide. Then the obtained Vilsmeier reagent was mixed with 1,1,2-trichloroethane at a mass ratio of 1:1 and cooled to -10~5℃ to obtain the reaction raw material solution.

[0029] (2) The reaction raw material liquid pre-cooled to -10~5℃ and the DMF solution of sucrose-6-acetate (the mass concentration of sucrose-6-acetate in the DMF solution of sucrose-6-acetate is 20~45%) are simultaneously introduced into the pipeline mixer at a feed volume flow ratio of 5~10:1. After being mixed evenly, the mixture is sent to a three-stage continuous reactor for high-temperature chlorination reaction and removal of the by-product hydrogen chloride. The temperatures of each reactor in the three-stage continuous reactor are set to 75~85℃, 90~100℃, and 105~115℃ respectively, and the residence times are set to 20~120min, 20~90min, and 20~90min respectively.

[0030] (3) The chlorinated liquid after the high-temperature chlorination reaction is pumped into a ripening reactor at 105~115℃ and left for 20~120min to ensure complete chlorination and further remove hydrogen chloride. Then the chlorinated reaction liquid is cooled to 0~20℃ by a cooler.

[0031] (4) Pass the chlorination reaction solution cooled in step (3) into the first-stage neutralization reactor, let it stand for 5 to 60 minutes, and use an ammonia solution with a volume concentration of 20 to 25% to adjust the pH of the neutralized material to 8 to 10.

[0032] (5) Pass the neutralized material from step (4) into a neutralization cooler. After cooling to 0~20℃, send it into a secondary neutralization reactor and hold for 5~45 minutes. Adjust the pH to 7~7.5 using a sulfuric acid solution with a volume concentration of 40-50% to obtain the target product.

[0033] The three-stage continuous reactor is composed of one or a combination of three of the following: tubular reactor, batch reactor, oscillating flow reactor, or microchannel reactor.

[0034] The maturation reactor is one of the following: tubular reactor, batch reactor, oscillating flow reactor, or microchannel reactor.

[0035] Both the primary neutralization reactor and the secondary neutralization reactor are one of the following: tubular reactor, oscillating flow reactor, or microchannel reactor.

[0036] To make the content of this invention easier to understand, the technical solution of this invention will be further described below with reference to specific embodiments, but this invention is not limited thereto.

[0037] Example 1

[0038] A continuous chlorination method for sucrose-6-acetate, the process steps of which are as follows:

[0039] 1) 86.92 kg (0.7306 kmol) of SOCl2 was placed in a three-necked flask and pre-cooled in a cold trap at 0 °C. Then, it was mixed with 93.87 kg (0.7890 kmol) of DMF in a Vilsmeier reagent preparation vessel. The mixed solution was then heated to 45 °C to remove sulfur dioxide, yielding the Vilsmeier reagent. The sulfur dioxide tail gas after removal was condensed, dried, and compressed to obtain the sulfur dioxide product.

[0040] 2) The obtained Vilsmeier reagent with a mass flow rate of 50 kg / h was mixed with 1,1,2-trichloroethane with a mass flow rate of 75 kg / h and cooled to -5℃~0℃ to obtain the reaction raw material solution;

[0041] 3) A 30% (w / w) DMF solution of sucrose-6-acetate was mixed with the obtained reaction raw material solution via a pipeline mixer at feed flow rates of 50 L / h and 350 L / h, respectively. The mixture was then fed into a three-stage continuous reactor for high-temperature chlorination. The temperatures of the reactors in the three-stage continuous reactor were set to 85℃, 100℃, and 110℃, and the residence times were set to 90 min, 60 min, and 60 min, respectively. The hydrogen chloride gas produced by the reaction was collected separately.

[0042] 4) The chlorinated liquid after the high-temperature chlorination reaction is pumped into a 109℃ ripening reactor and held for 90 minutes to ensure the chlorination reaction is complete and the hydrogen chloride gas is completely removed. Then, the chlorinated reaction liquid is cooled to 10℃ through a cooler. The two streams of hydrogen chloride tail gas collected are condensed, dried and compressed to obtain the hydrogen chloride product.

[0043] 5) Pass the cooled chlorination reaction solution into the primary neutralization reactor, let it stand for 30 minutes, and use a 20% ammonia solution to adjust the pH of the neutralized material to 9.5 (control the discharge rate and feed rate to keep the liquid level stable).

[0044] 6) Pass the neutralized material into a neutralization cooler, cool it to 10°C, and then send it into a secondary neutralization reactor. Let it stand for 20 minutes, and adjust the pH to 7 using a 50% sulfuric acid solution to obtain the target product.

[0045] Example 2

[0046] The purified sucrose-6-acetate obtained according to the method disclosed in CN 114437146A was used as the raw material and prepared according to Example 1.

[0047] Comparative Example 1

[0048] The batch chlorination reaction was carried out using the traditional one-pot in-situ preparation method of Vilsmiere's reagent. The procedure is as follows:

[0049] Weigh 258.30 g (1.9363 mol) of 1,1,2-trichloroethane and 86.92 g (0.7306 mol) of SOCl2 into a three-necked flask and mix by stirring at -10℃. A DMF solution containing 33.56 g (0.08732 mol) of sucrose-6-acetate (containing 65.48 g, 0.8958 mol of DMF) was slowly added dropwise to the above solution while continuously stirring (keeping the temperature below 5°C). After the addition was completed, the solution was stirred at a low temperature for 30 min. The mixture was then transferred to room temperature and stirred thoroughly for 40 min. The temperature was then raised to 85°C for 30 min and held for 60 min. The temperature was then raised to 100°C for 30 min and held for 60 min. Finally, the temperature was raised to 110°C for 45 min and held for 100 min. After the reaction was completed, the chlorinated reaction solution was cooled to -10°C. A 20 wt% ammonia solution was added to adjust the pH to 9.2, and the temperature was kept below 5°C while stirring for 10 min. Finally, a 50 wt% sulfuric acid solution was added to adjust the pH to 7 to obtain the target product.

[0050] Comparative Example 2

[0051] The process of preparing Vilsmiere's reagent in advance before intermittent chlorination is as follows:

[0052] 1) Weigh 86.92 g (0.7306 mol) of SOCl2 into a three-necked flask, pre-cool it in a cold trap at 0 °C, then add 93.87 g (0.7890 mol) of DMF to the SOCl2 and stir continuously. Then heat the mixed solution to 45 °C to remove sulfur dioxide and obtain Vilsmeier reagent.

[0053] 2) The Vilsmeier reagent obtained above was mixed with 258.30 g (1.9363 mol) of 1,1,2-trichloroethane and cooled to -5℃~0℃ to obtain the reaction raw material solution;

[0054] 3) A DMF solution containing 33.56 g (0.08732 mol) of sucrose-6-acetate (containing 30.30 g, 0.2547 mol of DMF) was mixed with the obtained reaction raw material solution through a pipeline mixer at feed volume flow rates of 0.5 mL / min and 3.5 mL / min, respectively. The mixer used chilled water for heat exchange.

[0055] 4) Heat the mixture obtained in step 3) to 85°C for 30 min and maintain for 60 min; then heat to 100°C for 30 min and maintain for 60 min; finally heat to 110°C for 45 min and maintain for 100 min; after the reaction is complete, cool the chlorination reaction solution to -10°C, add 20 wt% ammonia solution to adjust the pH to 9.2, and stir for 10 min while maintaining the temperature below 5°C. Then add 50 wt% sulfuric acid solution to adjust the pH to 7 to obtain the target product.

[0056] The yields of the products obtained in the examples and comparative examples are shown in Table 1.

[0057] Table 1

[0058]

[0059] The results in Table 1 clearly show that:

[0060] (1) Preparing Vilsmiere reagent in advance can avoid side reactions caused by SOCl2, so that the main reaction in the process is the substitution reaction of chlorine, which improves the product selectivity and thus significantly increases the product yield.

[0061] (2) Changing the intermittent operation to continuous chlorination and removing the acidic tail gas from the reaction system in time can avoid side reactions caused by dissolving acidic substances in the solution and help improve the yield.

[0062] (3) Using purified sucrose-6-acetic acid ester for the reaction results in a higher yield.

[0063] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A method for chlorinating sucrose-6-acetic acid ester, characterized in that, Includes the following steps: (1) DMF and thionyl chloride were introduced into the Vilsmeier reagent preparation vessel for mixing and the temperature was raised to 45~55℃ to remove sulfur dioxide. Then the obtained Vilsmeier reagent was mixed with 1,1,2-trichloroethane and cooled to -10~5℃ to obtain the reaction raw material solution. (2) The reaction raw material solution obtained in step (1) and the DMF solution of sucrose-6-acetate are simultaneously introduced into the pipeline mixer for mixing. After being mixed evenly, the mixture is sent to a three-stage continuous reactor for high-temperature chlorination reaction and removal of the by-product hydrogen chloride. (3) The chlorinated liquid after the high-temperature chlorination reaction is fed into the ripening reactor for a second reaction to ensure complete chlorination and further remove hydrogen chloride. The chlorinated reaction liquid is then cooled to 0~20℃ by a cooler. (4) The chlorination reaction solution cooled in step (3) is sent to the first-stage neutralization reactor, and the pH of the neutralized material is adjusted to 8~10 using ammonia solution. (5) The material after neutralization in step (4) is fed into a neutralization cooler and cooled to 0~20℃ before being sent to a secondary neutralization reactor. The pH is adjusted to 7~7.5 using sulfuric acid solution to obtain the target product. The three-stage continuous reactor mentioned in step (2) is composed of one or a combination of three of the following: tubular reactor, batch reactor, oscillating flow reactor, or microchannel reactor; during the high-temperature chlorination reaction, the temperatures of each reactor in the three-stage continuous reactor are 75~85℃, 90~100℃, and 105~115℃ respectively, and the residence times of each reactor are 20~120min, 20~90min, and 20~90min respectively; the feed volume flow ratio of the reaction raw material liquid to the DMF solution of sucrose-6-acetate used in step (2) is 5~10:1, and the mass concentration of sucrose-6-acetate in the DMF solution of sucrose-6-acetate is 20~45%; both the DMF and the reaction raw material liquid used need to be pre-cooled to -10~5℃; The maturation reactor mentioned in step (3) is one of a tubular reactor, a batch reactor, an oscillating flow reactor or a microchannel reactor, with a set temperature of 105~115℃ and a residence time of chlorination liquid in it of 20~120min; The primary neutralization reactor mentioned in step (4) is one of a tubular reactor, an oscillating flow reactor, or a microchannel reactor; the residence time of the chlorination reaction solution in the primary neutralization reactor is 5-60 min; and the mass concentration of the ammonia solution used is 20-30%. The secondary neutralization reactor mentioned in step (5) is one of a tubular reactor, an oscillating flow reactor, or a microchannel reactor; the residence time of the material in the secondary neutralization reactor is 5 to 45 minutes; and the mass concentration of the sulfuric acid solution used is 40 to 60%.

2. The chlorination method for sucrose-6-acetic acid ester according to claim 1, characterized in that, The molar ratio of DMF to thionyl chloride used in step (1) is 1~1.5:

1.

3. The chlorination method for sucrose-6-acetate according to claim 1, characterized in that, The mass ratio of Vilsmeier reagent to 1,1,2-trichloroethane used in step (1) is 1:1~3.

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