WO2022140931A1 - 蔗糖-6-羧酸酯的氯代方法 - Google Patents

蔗糖-6-羧酸酯的氯代方法 Download PDF

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WO2022140931A1
WO2022140931A1 PCT/CN2020/140221 CN2020140221W WO2022140931A1 WO 2022140931 A1 WO2022140931 A1 WO 2022140931A1 CN 2020140221 W CN2020140221 W CN 2020140221W WO 2022140931 A1 WO2022140931 A1 WO 2022140931A1
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carboxylate
reaction
solution
sucrose
solid phosgene
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PCT/CN2020/140221
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English (en)
French (fr)
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WO2022140931A9 (zh
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张从勇
赵金刚
卜永峰
陈朝晖
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安徽金禾实业股份有限公司
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Priority to CN202080004020.XA priority Critical patent/CN112996798A/zh
Priority to PCT/CN2020/140221 priority patent/WO2022140931A1/zh
Publication of WO2022140931A1 publication Critical patent/WO2022140931A1/zh
Publication of WO2022140931A9 publication Critical patent/WO2022140931A9/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • the invention belongs to the technical field of chemical manufacturing, and in particular relates to a method for chlorination of sucrose-6-carboxylate.
  • Sucralose has high sweetness, good taste and high safety, and has been widely used; and without any calories, it can be provided to obese patients, diabetic patients, cardiovascular disease patients and the elderly for use; in addition, it will not cause caries, Helps with dental health.
  • chlorination reagents include thionyl chloride, phosgene, bis(trichloromethyl) carbonate, sulfonyl chloride, oxalyl chloride, Phosphorus oxychloride, phosphorus pentachloride and Vilsmeier reagent, etc., wherein, Vilsmeier reagent is a kind of salt generated by the reaction of SOCl 2 , PCl 3 , COCl 2 and other reagents with DMF at low temperature. Relatively speaking, the Vilsmeier reagent method has attracted much attention because of its high selectivity.
  • the phosgene method has a natural advantage because there is no waste acid and waste salt waste liquid to be treated.
  • liquid phosgene such as SOCl 2 , PCl 3 , COCl 2 reacts with DMF and sucrose-6-carboxylate to form huge agglomerates (CN105153247B), causing difficulty in stirring, local filtration and chlorination, and even Carbonization, etc. need to be improved.
  • the present application is made in order to provide a preparation method of sucrose-6-carboxylate which overcomes the above problems or at least partially solves the above problems.
  • the present application has been made in order to provide a method for the chlorination of sucrose-6-carboxylates which overcomes the above problems or at least partially solves the above problems.
  • the reaction solution preparation step dissolving solid phosgene in the first solvent to obtain a solid phosgene solution, dissolving sucrose-6-carboxylate in the second solvent to obtain a carboxylate solution;
  • the reactant mixing step adding a catalyst to the carboxylate solution, stirring until the catalyst is completely dissolved, and then slowly adding the solid light dropwise to the carboxylate solution containing the catalyst at a first preset temperature. gas solution;
  • the reactant mixing step is operated multiple times to obtain a reaction mixture solution
  • the step of controlling reaction conditions keeping the reaction mixture solution at a first preset temperature for a first preset time, and then raising the temperature to a second preset temperature and maintaining the reaction for a second preset time so that the chlorination reaction is performed;
  • Post-processing step adding a pH value adjuster to the reaction mixture solution to adjust the pH value in the range of 7-9.
  • sucrose-6-carboxylate prepared by the above method.
  • the beneficial effects of the present application are: the present application adopts solid phosgene to replace the traditional Vilsmeier reagent, while avoiding the current situation of the Vilsmeier reagent and DMF agglomeration in the prior art, the safety, reliability and environmental friendliness of the reaction are improved, The cost of the chlorination reaction of sucrose-6-carboxylate is reduced; at the same time, during the reaction process, the present application adds the catalyst and the solid phosgene solution to the carboxylate solution several times, and controls the chlorination reaction conditions to be The stepwise temperature rise makes the chlorination reaction conditions of sucrose-6-carboxylate mild, and the process operation is convenient; the selectivity of trichlorides is high, the side reactions are few, and the product yield is high; the discharge amount of waste gas and waste liquid is small.
  • the present application adopts solid phosgene to replace the traditional Vilsmeier reagent, avoids the current situation of the Vilsmeier reagent and DMF agglomeration in the prior art, and at the same time, the chlorination process has high conversion rate, simple waste gas, less waste water and simple post-treatment.
  • the catalyst and the dissolved solid phosgene solution are added to the carboxylate solution in batches, and the temperature is stepped up, so that the reaction conditions are mild, the mass transfer is uniform, the reaction is thorough, and the yield is high.
  • a method for chlorination of sucrose-6-carboxylate comprising:
  • the preparation steps of the reaction solution dissolving solid phosgene in a first solvent to obtain a solid phosgene solution, and dissolving sucrose-6-carboxylate in a second solvent to obtain a carboxylate solution.
  • Traditional liquid phosgene such as SOCl 2
  • SOCl 2 is a highly toxic liquid, reacts violently with water, is highly corrosive, and has high production safety hazards.
  • solid phosgene is used to replace traditional liquid phosgene, and the solid phosgene is convenient for transportation and storage, and there is no distillation process in the production process, and the safety and controllability are strong.
  • a solid phosgene solution is obtained by dissolving solid phosgene in a first solvent, wherein the first solvent is a solvent that is easily soluble and more environmentally friendly, instead of DMF in the prior art, to achieve the purpose of reducing pollution.
  • the carboxylate solution is obtained by dissolving the raw material sucrose-6-carboxylate in the second solvent.
  • the first solvent and the second solvent may be the same or different, and it is recommended to use the same solvent to reduce the species of substances in the entire reaction system and the steps of post-processing.
  • the reactant mixing step adding a catalyst to the carboxylate solution, stirring until the catalyst is completely dissolved, and then slowly adding the solid phosgene solution dropwise to the carboxylate solution containing the catalyst at a first preset temperature;
  • the mixing step is performed for several times until the dropwise addition of a predetermined amount of the catalyst and the solid phosgene solution is completed to obtain a reaction mixed solution.
  • the reaction condition control step keeping the reaction mixture solution at a first preset temperature for a first preset time, and then raising the temperature to a second preset temperature and holding the reaction for a second preset time to perform the chlorination reaction.
  • Adding the catalyst and the solid phosgene solution several times can ensure that the chlorination reaction will not be too violent, and can ensure that the catalyst, solid phosgene and carboxylate solution are evenly mixed, mass transfer and heat transfer are uniform, and local insufficiency will not occur.
  • the selectivity of trichloride is higher and the product yield is higher.
  • the present application controls the chlorination reaction conditions to be stepwise heating, that is, the reaction mixture solution is kept at a first preset temperature for a first preset time, and then heated to a second preset temperature and kept for a second preset time for the reaction to proceed. Chlorination reaction.
  • the catalyst can be any catalyst that can realize the chlorination reaction, such as a basic catalyst.
  • the application divides the chlorination reaction into two stages, corresponding to the first preset time and the second preset time respectively.
  • the chlorination reaction of gas and sucrose-6-carboxylate is divided into two stages, namely the complex formation stage and the hydroxyl removal stage.
  • the present application sets different reaction conditions according to different reaction stages, so that the reaction conditions are more specific. It also contributes to the forward progress of the reaction, improves the selectivity of trichlorides, and improves the product yield.
  • the present application adopts solid phosgene to replace the traditional Vilsmeier reagent, which avoids the current situation of the Vilsmeier reagent and DMF agglomerating in the prior art, improves the safety, reliability and environmental friendliness of the reaction, reduces the sucrose -The cost of the chlorination reaction of 6-carboxylate; at the same time, during the reaction process, the present application adds the catalyst and the solid phosgene solution to the carboxylate solution several times, and divides the chlorination reaction conditions into stages according to the reaction characteristics The control is carried out to make the chlorination reaction conditions of sucrose-6-carboxylate mild, and the process operation is convenient; the selectivity of trichlorides is high, the side reactions are few, and the product yield is high; and the discharge amount of waste gas and waste liquid is small.
  • the method for chlorination of sucrose-6-carboxylate further comprises: a post-processing step: adding a pH value adjuster to the reaction mixture solution obtained above, and adjusting the pH value in the range of 7-7 9.
  • a post-processing step adding a pH value adjuster to the reaction mixture solution obtained above, and adjusting the pH value in the range of 7-7 9.
  • sucralose-6-carboxylate crystals with higher purity can also be obtained by filtration and crystallization, for example, ethyl acetate is used for crystallization.
  • a pH value adjuster is added to the solution obtained by the chlorination reaction, and the pH is adjusted to be in the preset range of alkalinity, because the chlorination reaction solution of sucrose-6-carboxylate is The chlorinated product in the solution can be hydrolyzed to the target product only when the pH value is within the preset range of alkalinity.
  • the preset alkalinity range is a description, not an absolute alkalinity range. In this application, it can be considered as a range of partial alkalinity near neutral, for example, the preset alkalinity range is 7-9.
  • the solution obtained by the chlorination reaction is cooled to 0-20° C., and ammonia water is slowly added dropwise to adjust the pH value to a preset alkaline range.
  • the solution obtained by the chlorination reaction is cooled to 30-50° C., ammonia gas is slowly introduced, and the pH value is adjusted to a preset range of alkalinity, and the preset range of alkalinity is 7-9.
  • the conditions for adding the pH adjuster are set according to the type of the pH adjuster.
  • the addition temperature can be 0 to 20°C. If the temperature at which the ammonia water is added is lower than 0°C, the addition conditions are too high. Mild, the neutralization reaction is too slow, and the probability of side reactions is above, which will cause the formation of by-products; if the temperature of ammonia water is higher than 20 °C, the reaction conditions are too intense, and the neutralization reaction is too fast, because the neutralization reaction is exothermic. If the temperature is too high, the reaction liquid may even be partially boiled.
  • the addition temperature can be 30 to 50°C.
  • the addition conditions are too mild, the neutralization reaction is too slow, and the probability of occurrence of side reactions is as described above. , which will cause the formation of by-products; if the temperature at which the ammonia gas is added is higher than 50 °C, the reaction conditions are too intense, and the neutralization reaction is too fast. Since the neutralization reaction is an exothermic reaction, an excessively high temperature may even cause a partial explosion of the reaction solution. boil.
  • the specific method for pH value adjustment is to slowly add a small amount of ammonia water dropwise to the solution obtained by the chlorination reaction, carry out preliminary neutralization, and then introduce ammonia gas to adjust the pH value to 7-9.
  • the hydrolysis side reaction under alkaline conditions can also avoid the problems of poor absorption effect and insufficient reaction simply by using ammonia gas.
  • the addition conditions of ammonia water and ammonia gas can be as described above, and the addition amount can be selected according to actual needs. The amount of ammonia water is less than the amount of ammonia gas. 1:100.
  • the type of solid phosgene is not limited, and in other embodiments, the solid phosgene is trichloromethyl chloroformate (diphosgene) and/or bis(trichloromethane) base) carbonate (triphosgene).
  • the amount of solid phosgene is not limited. In other embodiments, the mass amount of solid phosgene is 1 to 8 times the mass amount of sucrose-6-carboxylate, In some embodiments, it is 2-4 times.
  • the mass dosage of solid phosgene is less than 1 time of the mass dosage of sucrose-6-carboxylate, the dosage of solid phosgene is too small, resulting in incomplete chlorination reaction, and more monochloride and dichloride in the generated product If the mass consumption of solid phosgene is greater than 8 times of the mass consumption of sucrose-6-carboxylate, then the consumption of solid phosgene is excessive, resulting in excessive chlorination, generating polychlorinated substances, and the reactants are complex and difficult to separate.
  • a solid phosgene solution is formed, wherein the solid phosgene accounts for 5-50 wt % of the solid phosgene solution, and in some embodiments is 20 ⁇ 40wt%.
  • the concentration of the solid phosgene solution is too low, so that the total volume of the solid phosgene solution is too large, and the usage amount of the first solvent is too large, so that the total volume of the reaction solution is too large,
  • the time of adding to the sucrose-6-carboxylate solution is too long, and the probability of the collision between the solid phosgene and the sucrose-6-carboxylate is reduced, the complex is not easily formed, and the reaction is difficult;
  • the solid phosgene is more than 50wt% of the solid phosgene solution, the concentration of the solid phosgene solution is too high, resulting in a large local solid phosgene concentration when the solid phosgene is added to the sucrose-6-carboxylate solution, and it is easy to locally generate para-chlorinated phosgene.
  • Intermediate complexes which in turn generate polychlorinated products.
  • the types and amounts of the first solvent and the second solvent are not limited.
  • the first solvent is one or more of acetonitrile, trichloroethane, dichloromethane, dichloroethane, and trichloromethane, in other embodiments acetonitrile;
  • the second solvent is one or more of acetonitrile, dichloromethane, trichloroethane, dichloroethane and trichloromethane, and in other embodiments, it is acetonitrile and/or trichloroethane.
  • the commonly used solvent is DMF or DMAC.
  • DMF liquid phosgene
  • PCl3 liquid phosgene
  • DMF highly polluting and difficult to handle.
  • the above easily dispersible solvent is used instead of DMF or DMAC, which can not only avoid agglomeration, but also achieve the purpose of reducing pollution.
  • the first solvent is different from the second solvent, and in other embodiments, the first solvent and the second solvent are the same, and in the case where the first solvent and the second solvent are the same, the reaction can be reduced
  • the number of species in the system reduces the difficulty of post-processing and is helpful for subsequent solvent recovery and reuse.
  • the amount of the second solvent is not limited. In other embodiments of the present application, based on the mass amount of sucrose-6-carboxylate, the volumetric amount of the second solvent is The mass dosage of sucrose-6-carboxylate is 1-10 times, and in some other embodiments of the present application, it is 2-6 times.
  • the volume consumption of the second solvent is less than 1 times of the mass consumption of sucrose-6-carboxylate, the use amount of the second solvent is too large, so that the total volume of the reaction solution is too large, and the solid phosgene and The probability of sucrose-6-carboxylate collision is reduced, the complex is not easily formed, and the reaction is difficult; if the volume dosage of the second solvent is more than 10 times the mass dosage of the sucrose-6-carboxylate, the If the dosage is too small, and the local concentration of sucrose-6-carboxylate is too high, the amount of solid phosgene is insufficient, resulting in insufficient chlorination.
  • the type of catalyst is not limited.
  • the catalyst is triethylamine, trimethylamine, triphenylamine, N,N-dimethylaniline, N,N-diphenylamine Ethylaniline, DMF or DMAC, in yet other embodiments triethylamine.
  • Organic amines are relatively mild initiators for chlorination reactions, which can effectively promote the removal of hydroxyl groups at 4, 1', 6' positions without excessive removal of hydroxyl groups at other positions.
  • DMF or DMAC also has a good initiating effect on the chlorination reaction.
  • the amount of catalyst is not limited. In other embodiments, based on the mass amount of sucrose-6-carboxylate, the volume amount of the catalyst is sucrose-6-carboxylate. 0.01 to 0.5 times the mass amount of , and in other embodiments, 0.1 to 0.4 times. If the volume dosage of the catalyst is less than 0.01 times the mass dosage of the sucrose-6-carboxylate, the amount of the catalyst is too small, resulting in whether the reaction can be effectively initiated, or the chlorination is incomplete, and it is easy to generate monochloride and dichloride.
  • Chloride if the volume dosage of the catalyst is more than 0.5 times the mass dosage of sucrose-6-carboxylate, the catalyst dosage is too much, which on the one hand causes unnecessary waste, on the other hand, causes excessive removal of hydroxyl groups, resulting in Polychlorinated substances, difficult to separate.
  • the conditions for dropping the catalyst and the solid phosgene solution are not limited. In other embodiments, the dropping times of the catalyst and the solid phosgene solution are 2-10 times, The total duration of the dropwise addition of the gas solution is not less than 1 hour, and the first preset temperature is 0-25°C.
  • the catalyst and solid phosgene solution are divided into small amounts and added to the carboxylate solution several times.
  • the concentration of the local catalyst or the solid phosgene solution is too large.
  • the total time for the dropwise addition of the catalyst and the solid phosgene solution is not less than 1 h, and the number of times for the dropwise addition of the catalyst and the solid phosgene solution is not less than 2 times. It is best to complete the dropwise addition within 10 times.
  • the temperature is controlled to a certain extent, that is, the dropwise addition is performed at a certain temperature, and the temperature is recorded as the first preset temperature.
  • the first preset temperature is 0 to 25° C. If the temperature is lower than 0° C., the temperature is too low, the molecular kinetic energy in the solid phosgene solution and the sucrose-6-carboxylate solution is too small, and it is difficult to form complexes. If the temperature is higher than 25°C, the temperature is too high, and the formed complex intermediate is too active, the chemical bond is easily broken, and the chlorinated product cannot be formed.
  • the chlorination reaction conditions are not limited. With reference to the prior art, the chlorination reaction can take place as the criterion. In other embodiments, the chlorination reaction conditions are divided into two stages for control, and the first preset temperature is maintained for a period of time, and this period of time is recorded as the first preset time, wherein the first preset temperature That is, the dropping temperature of the catalyst and the solid phosgene solution, in some embodiments, is 0-25° C., at this temperature, it is maintained for 1-24 hours, and in other embodiments, it is 2-8 hours. This process is the first stage of the chlorination reaction, which is the process of complex intermediate formation.
  • the temperature of the entire reaction system is raised to the second preset temperature and maintained for a period of time, and this period of time is recorded as the second preset time.
  • the second preset temperature is 30-90°C
  • the second preset time is 2-48h
  • the second preset temperature is 60-80°C
  • the second preset time is 8-16h. If the second preset temperature is lower than 30°C and the second preset time is less than 2h, the temperature is too low and the reaction time is too short, resulting in too low removal rate of hydroxyl groups of sucrose-6-carboxylate and insufficient chlorination.
  • sucrose-6-carboxylate which can be commercially available, or can be produced by any one of the prior art, and sucrose-6-carboxylate can be sucrose-6-acetate , sucrose-6-benzoate, etc.
  • the organic tin monoester method can be used, that is, sucrose-6-carboxylate is obtained by dehydration reaction of sucrose and organic tin compounds, and then acylation with acid or acid anhydride.
  • the organotin compound may be selected from 1,3-bis(hydrocarbyl)-1,1,3,3-tetra-(hydrocarbyl)distannoxane, bis(hydrocarbyl)oxide ) tin, 1,3-diacyloxy-1,1,3,3-tetra-(hydrocarbyl)distannoxane and 1-acyloxy-1,1,3,3-tetra-(hydrocarbyl)di any of the stannoxanes, in other embodiments 1,3-diacyloxy-1,1,3,3-tetra-(hydrocarbyl)distannoxane, in still other embodiments 1,3-Diacetoxy-1,1,3,3-tetrabutyldist
  • the alkoxy group can be an alkoxy group or a phenoxy group, and in some embodiments, it is a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, and an n-pentoxy group Or n-hexyloxy, in other embodiments methoxy;
  • the hydrocarbon group in the organotin compound structure can be an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group, in some embodiments an alkyl group, in another n-butyl in some embodiments.
  • the organotin monoester method has economical and easy-to-obtain raw materials, high selectivity, and simple production process, and is widely used in the prior art.
  • the DMF content of sucrose-6-carboxylate before drying is less than 50 wt % and the water content is less than 0.1 wt %. In other embodiments , the DMF content is below 30wt%, and the water content is below 200ppm.
  • sucrose-6-carboxylate is not limited, and in other embodiments, it is sucrose-6-acetate, sucrose-6-butyrate, sucrose-6- Paraben, sucrose-6-fatty acid ester, sucrose-6-laurate.
  • sucrose-6-acetate and sucrose-6-benzoate can be used as important intermediates in the synthesis of sweetener sucralose.
  • the reaction kettle is hydraulically fed into another reactor. Turn on the heat transfer oil circulation of the reaction kettle, heat up to the second preset temperature (70-75° C. in the kettle), and stir and keep warm for 12 hours.
  • the reaction solution was released after cooling down naturally.
  • Ammonia gas was slowly introduced into the reaction solution at room temperature, and the pH value was adjusted to about 8.
  • the solid impurities are removed by means of pressure filtration.
  • the solvent was evaporated, and 1000 mL of water and 500 mL of ethyl acetate were added for crystallization to obtain sucralose-6-acetate.
  • the obtained products are listed in Table 1.
  • the calculation method of the yield is the mass ratio of the purified sucralose-6-acetate to the mass of the sucralose-6-acetate, and the algorithm in the following embodiments is the same.
  • Example 1 The tail gas in Example 1 was absorbed in three stages, 400 mL of acetonitrile was used for each stage, and the absorption temperature was -10°C. Dissolve 350 g of diphosgene with primary and secondary absorption liquids to obtain two solid phosgene solutions.
  • the reaction kettle is hydraulically fed into another reactor. Turn on the heat-conducting oil circulation of the reaction kettle, heat up to the second preset temperature (70-75° C. in the kettle), stir and keep warm for 8 hours.
  • the reaction kettle is hydraulically fed into another reactor. Turn on the heat transfer oil circulation of the reaction kettle, heat up to the second preset temperature (105-115° C. in the kettle), stir and keep warm for 4 hours.
  • reaction kettle After the dropwise addition was completed, the mixture was stirred and kept for 6 hours. After the heat preservation is completed, the reaction kettle is hydraulically fed into another reactor. Turn on the heat-conducting oil circulation of the reaction kettle, heat up to a predetermined reaction temperature (105-115° C. in the kettle), stir and keep warm for 4 hours.
  • a predetermined reaction temperature 105-115° C. in the kettle
  • the reaction solution was released after cooling down naturally.
  • Ammonia gas was slowly introduced into the reaction solution at room temperature, and the pH value was adjusted to about 8.
  • the solid impurities were removed by means of pressure filtration. Let stand for 1-2 hours, evaporate the solvent, add 400 mL of water and 200 mL of ethyl acetate to crystallize to obtain a sucralose-6-acetate product, and the obtained products are listed in Table 1.
  • the calculation method of the yield is the mass ratio of the purified sucralose-6-acetate to the sucrose equivalent.
  • sucrose-6-acetate sucrose-6-acetate equivalent 42 g
  • reaction kettle After the dropwise addition was completed, the mixture was stirred and kept for 6 hours. After the heat preservation is completed, the reaction kettle is hydraulically fed into another reactor. Turn on the heat-conducting oil circulation of the reaction kettle, heat up to a predetermined reaction temperature (105-115° C. in the kettle), stir and keep warm for 4 hours.
  • a predetermined reaction temperature 105-115° C. in the kettle
  • the reaction solution was released after cooling down naturally.
  • Ammonia gas was slowly introduced into the reaction solution at room temperature, and the pH value was adjusted to about 8.
  • the solid impurities were removed by means of pressure filtration. Let stand for 1-2 hours, evaporate the solvent, add 400 mL of water and 200 mL of ethyl acetate to crystallize to obtain 15 g of sucralose-6-acetate product, the purity is 48% as measured by high performance liquid chromatography, and the pure sucralose is obtained 7.2 g of -6-acetate, the yield is 18.00%.
  • the calculation method of the yield is the mass ratio of the purified sucralose-6-acetate to the sucrose equivalent.
  • Example 2 It can be seen from Example 2 that the solvent used in the present application can be recycled and used after simple treatment, which significantly reduces the cost and reduces the discharge of waste liquid.
  • the present invention uses solid phosgene to replace the traditional Vilsmeier reagent;
  • the purpose of reducing pollution; on the other hand, the Vilsmeier reagent used in the prior art, such as SOCl 2 is a highly toxic liquid, which reacts violently with water, is highly corrosive, and has a high production safety hazard.
  • the solid phosgene used in this application is more convenient to transport and store, and there is no distillation process in the production process, and the safety and controllability is strong, which improves the safety of the reaction; on the other hand, the application has more advantages in environmental protection.
  • each ton of sucrose-6-carboxylate consumes about 2.5 tons of solid phosgene
  • Vilsmeier reagent such as SOCl or phosphorus oxychloride
  • Vilsmeier reagents are all above 4 tons, and the yield of solid phosgene method will increase by 10% or more, and the cost of raw materials will decrease significantly. Therefore, using the method of the present application can improve the yield, reduce consumption and three wastes, and reduce costs, and is very suitable for industrial production.

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Abstract

本申请提供了蔗糖-6-羧酸酯的氯代方法，包括：将固体光气溶解在第一溶剂中而得到固体光气溶液，将蔗糖-6-羧酸酯溶解在第二溶剂中而得到羧酸酯溶液；向羧酸酯溶液中加入催化剂，然后在第一预设温度下，向含有催化剂的羧酸酯溶液中缓慢滴加固体光气溶液；将反应物混合步骤操作多次，得到反应混合溶液；将反应混合溶液在第一预设温度下保持反应第一预设时间，然后升温至第二预设温度下保持反应第二预设时间使其进行氯代反应。本申请避免了Vilsmeier试剂与DMF结块的现状，提高了反应的安全性、可靠性、环境友好性，降低反应成本；同时反应条件温和，工艺操作方便；三氯代物选择性高、副反应少、产物收率高；废气废液的排放量小。

Description

蔗糖-6-羧酸酯的氯代方法 技术领域
本发明属于化工制造技术领域，具体涉及蔗糖-6-羧酸酯的氯代方法。
发明背景
三氯蔗糖甜度高、口感好、安全性高，己被广泛使用；且无任何热量，可提供给肥胖病人、糖尿病患者、心血管疾病患者及老年人使用；此外，不会引起龋变，有助于牙齿健康。
在制备三氯蔗糖的过程中，所有的工艺都必须通过氯代过程，是整个工艺流程的关键步骤，是最复杂、最难控制的一步，该过程的转化率及选择性，直接影响最终产物的产率。蔗糖-6-羧酸酯生成三氯蔗糖的氯代反应中，仅需对4,1’,6’-三个位置进行氯代，否则会存在不充分氯代或过度氯代的情况，导致副产物非常多，产物复杂，分离难度高，收率低。
现有技术中，在蔗糖-6-羧酸酯的氯代反应中，普遍使用的氯代试剂有亚硫酰氯、碳酰氯、二(三氯甲基)碳酸酯、磺酰氯、草酰氯、三氯氧磷、五氯化磷以及Vilsmeier试剂等，其中，Vilsmeier试剂是由SOCl 2、PCl 3、COCl 2等试剂与DMF在低温下反应生成的一种盐。相对而言，Vilsmeier试剂法因为选择性比较高，而备受关注。而光气法因为无废酸废盐废液需要处理，用光气制备Vilsmeier试剂，然后进行蔗糖-6-羧酸酯的氯代反应具有天然的优势。但在反应过程中，SOCl 2、PCl 3、COCl 2等液体光气与DMF以及蔗糖-6-羧酸酯反应会形成巨大的结块(CN105153247B)，造成搅拌困难，局部过滤氯化，甚至发生炭化等需要改进。
需要说明的是，这里的陈述仅提供与本申请有关的背景信息，而不必然地构成现有技术。
发明内容
鉴于上述问题，提出了本申请以便提供一种克服上述问题或者至少部分地解决上述问题的一种蔗糖-6-羧酸酯的制备方法。
鉴于上述问题，提出了本申请以便提供一种克服上述问题或者至少部分地解决上述问题的蔗糖-6-羧酸酯的氯代方法。
根据本申请的一种蔗糖-6-羧酸酯的氯代方法，包括：
反应溶液制备步骤：将固体光气溶解在第一溶剂中而得到固体光气溶液，将蔗糖-6-羧酸酯溶解在第二溶剂中而得到羧酸酯溶液；
反应物混合步骤：向所述羧酸酯溶液中加入催化剂，并搅拌至所述催化剂完全溶解，然后在第一预设温度下，向含有催化剂的羧酸酯溶液中缓慢滴加所述固体光气溶液；
将所述反应物混合步骤操作多次，得到反应混合溶液；
反应条件控制步骤：将所述反应混合溶液在第一预设温度下保持反应第一预设时间，然后升温至第二预设温度下保持反应第二预设时间使其进行氯代反应；以及
后处理步骤：向所述反应混合溶液中加入pH值调节剂，调节pH值的范围在7～9。
根据本申请另一方面，提供一种蔗糖-6-羧酸酯，其是采用上述方法制得的。
本申请的有益效果在于：本申请采用固体光气代替传统的Vilsmeier试剂，避免了现有技术中Vilsmeier试剂与DMF结块的现状的同时，提高了反应的安全性、可靠性、环境友好性，降低了蔗糖-6-羧酸酯氯代反应的成本；同时在反应过程中，本申请将催化剂和固体光气溶液中分多次添加至羧酸酯溶液中，并将氯代反应条件控制为阶段性升温，使得蔗糖-6-羧酸酯氯代反应条件温和，工艺操作方便；三氯代物选择性高、副反应少、产物收率高；废气废液的排放量小。
上述说明仅是本申请技术方案的概述，为了能够更清楚了解本申请的技术手段，而可依照说明书的内容予以实施，并且为了让本申请的上述和其它目的、特征和优点能够更明显易懂，以下特举本申请的具体实施方式。
实施本发明的方式
下面将参照附图更详细地描述本申请的示例性实施例。虽然附图中显示了本申请的示例性实施例，然而应当理解，可以以各种形式实现本申请而不应被这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解本申请，并且能够将本申请的范围完整的传达给本领域的技术人员。
本申请的构思在于，采用Vilsmeier试剂对蔗糖-6-羧酸酯进行氯化反应时，一般会产生大量的HCl和SO 2(SOCl 2法制备)，且SOCl 2属剧毒液体，遇水反应剧烈，强烈腐蚀性，生产安全隐患较高。或者HCl和含磷废液(三氯化磷和三氯氧 磷法制备)；副产物想要综合利用需要分离，工艺复杂，且高盐废水多。本申请采用固体光气代替传统的Vilsmeier试剂，避免现有技术中Vilsmeier试剂与DMF结块的现状的同时，氯代工艺，转化率高，废气单纯，废水少，后处理简单。且将催化剂和溶解了的固体光气溶液分批次加入的羧酸酯溶液中，并阶梯式升温，使得反应条件温和、传质均匀、反应彻底、产率高。
根据本申请的一些实施例，提供了一种蔗糖-6-羧酸酯的氯代方法，包括：
反应溶液制备步骤：将固体光气溶解在第一溶剂中而得到固体光气溶液，将蔗糖-6-羧酸酯溶解在第二溶剂中而得到羧酸酯溶液。
传统的液体光气，如SOCl 2，属剧毒液体，遇水反应剧烈，强烈腐蚀性，生产安全隐患较高。本申请采用固体光气代替传统的液体光气，固体光气方便运输和保存，且在生产过程中不存在蒸馏过程，安全可控性强。
首先，将固体光气溶解在第一溶剂中而得到固体光气溶液，其中，第一溶剂为易溶且环保性更强的溶剂，代替现有技术中的DMF，达到以减少污染的目的。将原料蔗糖-6-羧酸酯溶解在第二溶剂中而得到羧酸酯溶液。
第一溶剂与第二溶剂可相同或者不同，推荐采用相同的溶剂，以减少整个反应体系中的物质种类，以及后处理的步骤。
反应物混合步骤：向羧酸酯溶液中加入催化剂，并搅拌至催化剂完全溶解，然后在第一预设温度下，向含有催化剂的羧酸酯溶液中缓慢滴加固体光气溶液；将反应物混合步骤操作多次，直至将预定量的催化剂和固体光气溶液滴加完毕，得到反应混合溶液。
反应条件控制步骤：将反应混合溶液在第一预设温度下保持反应第一预设时间，然后升温至第二预设温度下保持反应第二预设时间使其进行氯代反应。
将催化剂和固体光气溶液分多次添加能够保障氯代反应不会过于剧烈，且能够保障催化剂、固体光气与羧酸酯溶液均匀混合，传质、传热均匀，不会发生局部不充分氯代或过度氯代的情况，使得三氯代物选择性更高、产物收率高。
本申请控制氯代反应条件为阶梯式升温，即将反应混合溶液在第一预设温度下保持反应第一预设时间，然后升温至第二预设温度下保持反应第二预设时间使其进行氯代反应。
在第一预设时间内，固体光气与蔗糖-6-羧酸酯会逐渐形成一种络合物，在第二预设时间内，在催化剂的作用下，这个络合物会逐渐脱除羟基与催化剂形成的化 合物，从而生成三氯代的蔗糖-6-羧酸酯。其中，催化剂可实现氯代反应的催化剂均可，如碱性催化剂。
本申请根据固体光气与蔗糖-6-羧酸酯的氯代反应的原理与特性，将氯代反应分为两个阶段，分别对应第一预设时间和第二预设时间，由于固体光气与蔗糖-6-羧酸酯的氯代反应分为两个阶段，即络合物形成阶段和羟基脱除阶段，本申请根据不同的反应阶段设置不同的反应条件，使得反应条件更加具有针对性，且有助于反应的正向进行，提高三氯代物的选择性，提高产品收率。
由此可见，本申请采用固体光气代替传统的Vilsmeier试剂，避免了现有技术中Vilsmeier试剂与DMF结块的现状的同时，提高了反应的安全性、可靠性、环境友好性，降低了蔗糖-6-羧酸酯氯代反应的成本；同时在反应过程中，本申请将催化剂和固体光气溶液中分多次添加至羧酸酯溶液中，并根据反应特点将氯代反应条件分阶段进行控制，使得蔗糖-6-羧酸酯氯代反应条件温和，工艺操作方便；三氯代物选择性高、副反应少、产物收率高；废气废液的排放量小。
在本申请的一些实施例中，该蔗糖-6-羧酸酯的氯代方法还包括：后处理步骤：向上述得到的反应混合溶液中加入pH值调节剂，调节pH值的范围在7～9。另外，还可以经过滤、结晶，即可得到纯度较高的三氯蔗糖-6-羧酸酯晶体，如采用乙酸乙酯进行结晶。
由于在氯代反应过程中，使用了强的氯代试剂，在氯代保温阶段温度高，会产生一系列的副产物，如一氯代蔗糖-6-羧酸酯、二氯代蔗糖-6-羧酸酯、四氯代蔗糖-6-羧酸酯等，因此，在氯代反应结束后，通过需要用碱性物质对得到的氯代反应液进行中和。
在本申请的一些实施例中，在后处理步骤中，向氯代反应得到的溶液中加入pH值调节剂，调节pH在碱性预设范围，因为蔗糖-6-羧酸酯氯代反应液中的氯化产物只有在pH值在碱性预设范围内时才能水解为目标产物。需要说明的是，碱性预设范围是一种描述词语，并不是绝对的碱性范围，在本申请中，可以认为中性附近偏碱的范围，如碱性预设范围为7～9。
关于pH值调节的具体方法，在一些实施例中，将氯代反应得到的溶液降温到0～20℃，缓慢滴加氨水，调节pH值至碱性预设范围。在另一些实施例中，将氯代反应得到的溶液降温到30～50℃，缓慢通入氨气，调节pH值至碱性预设范围，碱性预设范围为7～9。
pH值调节剂的加入条件根据pH值调节剂的种类进行设定，当pH值调节剂为氨水时，加入温度可以为0～20℃，若氨水加入的温度低于0℃，则加入条件过于温和，中和反应过慢，副反应发生概率上述，会造成副产物的生成；若氨水加入的温度高于20℃，则反应条件过于激烈，中和反应过快，由于中和反应是放热反应，温度过高甚至会造成反应液局部爆沸。
当pH值调节剂为氨气时，加入温度可以为30～50℃，同理，若氨气加入的温度低于30℃，则加入条件过于温和，中和反应过慢，副反应发生概率上述，会造成副产物的生成；若氨气加入的温度高于50℃，则反应条件过于激烈，中和反应过快，由于中和反应是放热反应，温度过高甚至会造成反应液局部爆沸。
在又一些实施例中，pH值调节的具体方法为向氯代反应得到的溶液中缓慢滴加少量氨水，进行初步中和，然后通入氨气，调节pH值至7～9。
发明人发现先采用氨水对蔗糖-6-羧酸酯氯代反应液进行预处理，可以提高后续蔗糖-6-羧酸酯氯代反应液对氨气的吸收率，基于这一发现，本申请推荐先通过氨水或者少量的水对蔗糖-6-羧酸酯氯代反应液进行初步中和，再采用氨气中和，既能够避免直接采用氨水中和时三氯蔗糖-6-羧酸酯在碱性条件下的水解副反应，又能避免单纯采用氨气中和吸收效果差、反应不充分的问题。氨水和氨气的加入条件通以上所述即可，加入量可根据实际需要进行选择，氨水用量少于氨气用量，如氨水的质量用量与氨气的体积用量的比为1:10～1:100。
固体光气的种类、用量、固体光气溶液浓度
在本申请中的一些实施例中，对固体光气的种类不做限制，在另一些实施例中，固体光气为氯甲酸三氯甲酯(双光气)和/或双(三氯甲基)碳酸酯(三光气)。
在本申请中的一些实施例中，对固体光气的用量不做限制，在另一些实施例中，固体光气的质量用量为蔗糖-6-羧酸酯的质量用量的1～8倍，在有一些实施例中为2～4倍。若固体光气的质量用量小于蔗糖-6-羧酸酯的质量用量的1倍，则固体光气用量过少，导致氯代反应不完全，生成的产物中一氯代物和二氯代物偏多；若固体光气的质量用量大于蔗糖-6-羧酸酯的质量用量的8倍，则固体光气用量过多，导致氯代过度，生成多氯代物，且反应物复杂，分离困难。
在本申请中的一些实施例中，将固体光气溶解于第一溶剂后，形成了固体光气溶液中，其中固体光气占固体光气溶液的5～50wt％，在一些实施例中为20～40wt％。若固体光气少于固体光气溶液的5wt％，则固体光气溶液浓度过低，使得固体光气 溶液总体积过大，第一溶剂的使用量过大，使得反应液总体积过大，使得向蔗糖-6-羧酸酯溶液中加入的时间过长，且固体光气与蔗糖-6-羧酸酯碰撞的概率降低，络合物不易形成，造成反应困难；若固体光气多于固体光气溶液的50wt％，则固体光气溶液浓度过高，造成在固体光气在加入蔗糖-6-羧酸酯溶液中时，局部固体光气浓度多大，容易在局部生成对氯代的中间络合物，进而生成多氯代产物。
溶剂的种类和用量
在本申请的一些实施例中，对第一溶剂和第二溶剂的种类和用量均不作限制。在一些实施例中，第一溶剂为乙腈、三氯乙烷、二氯甲烷、二氯乙烷和三氯甲烷中的一种或多种，在另一些实施中为乙腈；在一些实施例中，第二溶剂为乙腈、二氯甲烷、三氯乙烷、二氯乙烷和三氯甲烷中的一种或多种，在另一些实施例中为乙腈和/或三氯乙烷。
在现有技术中，常用溶剂为DMF或DMAC，以DMF为例，其容易与PCl3等液体光气形成巨大的结块，且DMF污染性强，后处理困难。而本申请中，采用上述的易分散溶剂代替DMF或DMAC，既能避免结块，又能达到减少污染的目的。
在本申请的一些实施例中，第一溶剂与第二溶剂不同，在另一些实施例中，第一溶剂与第二溶剂相同，在第一溶剂与第二溶剂相同的情况下，能够减少反应体系中物种的数量，减少后处理的难度，有助于后续溶剂的回收再利用。
在本申请的一些实施例中，对第二溶剂的用量不做限制，在本申请的另一些实施例中，以蔗糖-6-羧酸酯的质量用量为基准，第二溶剂的体积用量为蔗糖-6-羧酸酯的质量用量的1～10倍，在本申请的又一些实施例中为2～6倍。与第一溶剂同理，若第二溶剂的体积用量小于蔗糖-6-羧酸酯的质量用量的1倍，第二溶剂的使用量过大，使得反应液总体积过大，固体光气与蔗糖-6-羧酸酯碰撞的概率降低，络合物不易形成，造成反应困难；若第二溶剂的体积用量多于蔗糖-6-羧酸酯的质量用量的10倍，则第二溶剂的用量过少，局部蔗糖-6-羧酸酯的浓度过高，则固体光气的量不足，造成氯代不充分的现象。
催化剂的种类和用量
在本申请的一些实施例中，对催化剂的种类不做限制，在另一些实施例中，催化剂为三乙胺、三甲胺、三苯胺、N，N-二甲基苯胺、N，N-二乙基苯胺、DMF或DMAC，在又一些实施例中为三乙胺。有机胺是用于氯代反应较为温和的引发剂，既能够有效促进4,1’,6’位置上羟基的脱除，又不会使得其他位置的羟基过分的 脱除，另外，经研究发现，DMF或DMAC对氯代反应也有较好的引发效果。
在本申请的一些实施例中，对催化剂的用量不做限制，在另一些实施例中，以蔗糖-6-羧酸酯的质量用量为基准，催化剂的体积用量为蔗糖-6-羧酸酯的质量用量的0.01～0.5倍，在又一些实施例中为0.1～0.4倍。若催化剂的体积用量少于蔗糖-6-羧酸酯的质量用量的0.01倍，则催化剂用量过少，导致能不能有效的引发反应，或者导致氯代不完全，容易生成一氯代物和二氯代物；若催化剂的体积用量多于蔗糖-6-羧酸酯的质量用量的0.5倍，则催化剂用量过多，一方面造成不必要的浪费，另一方面，造成羟基的过度脱除，生成多氯代物质，分离困难。
催化剂和固体光气滴加条件
在本申请的一些实施例中，对催化剂和固体光气溶液滴加条件不做限制，在另一些实施例中，催化剂与固体光气溶液的滴加次数为2-10次，催化剂与固体光气溶液的滴加总时长不少于1h，第一预设温度为0～25℃。
固体光气与蔗糖-6-羧酸酯形成络合物中间体是一个较为缓慢的过程，为了能够混合均匀，将催化剂和固体光气溶液分为少量多次加入羧酸酯溶液中，为了防止局部催化剂或固体光气溶液的浓度过大，在一些实施例中，催化剂与固体光气溶液的滴加总时长不少于1h，催化剂与固体光气溶液的滴加次数不少于2次，最好在10次之内滴加完毕。
在本申请的一些实施例中，在滴加催化剂和固体光气溶液时，对温度进行一定的控制，即在一定的温度下进行滴加，该温度记为第一预设温度，在一些实施例中，第一预设温度为0～25℃，若该温度低于0℃，则温度过低，固体光气溶液和蔗糖-6-羧酸酯溶液中的分子动能过小，不易形成络合物中间体；若该温度高于25℃，则温度过高，形成的络合物中间体由于过于活跃，化学键容易断裂，不能形成氯代产物。
氯代反应的条件控制
在本申请的一些实施例中，对氯代反应条件不做限制，参考现有技术中，以能够发生氯代反应为准即可。在另一些实施例中，将氯代反应条件分为两个阶段进行控制，在第一预设温度下，先维持一段时间，该段时间记为第一预设时间，其中第一预设温度即为催化剂和固体光气溶液的滴加温度，在一些实施例中为0～25℃，在该温度下，维持1～24h，在另一些实施例中为2～8h。这个过程是氯代反应的第一阶段，是络合物中间体形成的过程。
在第一预设时间结束后，将整个反应体系的温度升温至第二预设温度，并维持一段时间，该段时间记为第二预设时间，在一些实施例中，第二预设温度为30～90℃，第二预设时间为2～48h，在另一些实施例中，第二预设温度为60～80℃，第二预设时间为8～16h。若第二预设温度低于30℃，第二预设时间小于2h，则温度过低，反应时间过短，造成蔗糖-6-羧酸酯的羟基脱除速率过低，氯代不充分，容易形成一氯代物或二氯代物；若第二预设温度高于90℃，第二预设时间大于48h，则温度过高，反应时间过长，造成氯代过度，产物中多氯代物较多。
蔗糖-6-羧酸酯的来源
对于蔗糖-6-羧酸酯的来源本申请不做限制，可为市售，或者采用现有技术中的任一种进行生产，蔗糖-6-羧酸酯可为蔗糖-6-乙酸酯、蔗糖-6-苯甲酸酯等。
如可采用有机锡单酯法，即蔗糖-6-羧酸酯是由蔗糖与有机锡化合物经过脱水反应，再与酸或酸酐酰化得来。其中，在本申请的一些实施例中，有机锡化合物可选自1,3-二(烃氧基)-1,1,3,3-四-(烃基)二锡氧烷、氧化二(烃基)锡、1,3-二酰氧基-1,1,3,3-四-(烃基)二锡氧烷和1-酰氧基-1,1,3,3-四-(烃基)二锡氧烷中的任意一种，在另一些实施例中为1,3-二酰氧基-1,1,3,3-四-(烃基)二锡氧烷，在又一些实施例中为1,3-二乙酰氧基-1,1,3,3-四丁基二锡氧烷。在上述的有机锡化合物结构中，烃氧基可以为烷氧基或苯氧基，在一些实施例中为甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基或正己氧基，在另一些实施例中为甲氧基；有机锡化合物结构中的烃基可以为烷基、环烷基、芳基或芳烷基，在一些实施例中为烷基，在另一些实施例中为正丁基。
有机锡单酯法原料经济易得、选择性高、生成工艺简单，为现有技术广泛使用，有机锡单酯法制备蔗糖-6-羧酸酯的生产工艺科参考现有技术。在本申请的一些实施例中，作为本申请所使用的原料，蔗糖-6-羧酸酯在干燥前，其DMF含量为50wt％以下，水含量低于0.1wt％，在另一些实施例中，DMF含量为30wt％以下，水含量低于200ppm。
在本申请的一些实施例中，对蔗糖-6-羧酸酯的种类不做限定，在另一些实施例中为蔗糖-6-乙酸酯、蔗糖-6-丁酸酯、蔗糖-6-苯甲酸酯、蔗糖-6-脂肪酸酯、蔗糖-6-月桂酸酯。其中，蔗糖-6-乙酸酯和蔗糖-6-苯甲酸酯可以用作合成甜味剂三氯蔗糖的重要中间体。
本申请中涉及的测定方法
本申请中各实施例和对比例中各物质的纯度均采用高效液相色谱(High Performance Liquid Chromatography，HPLC)方法在下述条件下测得，在各个实施例中不再赘述。
高效液相色谱的分析测定条件：日本岛津高效液相色谱仪，配RID-10A示差折光检测，LC-10ADVP高压泵，CTO-10ASVP恒温箱；色谱柱：Agilent XDB C18柱(250mm×4.6mm，5μm)；流动相：甲醇-0.125％磷酸氢二钾水溶液(4:6)；柱温：30℃；流量：1.0mL/min。其中，需要甲醇(色谱纯)、磷酸氢二钾(分析纯)、超纯水、以及标准物质等，外标法测量含量。
实施例1
将已干燥好的200g原料蔗糖-6-乙酸酯(含量65.0wt％，DMF含量30wt％，含水量100ppm)放入至烧瓶中，开启搅拌，加入1000mL乙腈，升温至50℃溶解，约1小时。然后倒入5L反应釜内，再向反应釜加入三乙胺25mL，充分搅拌溶解。
称量氯甲酸三氯甲酯(双光气)250g加入圆底烧瓶中，加入400mL乙腈，室温溶解完全，得到双光气溶液。将双光气溶液倒入反应釜上的恒压滴液漏斗。开启冷媒循环，降温到第一预设温度(釜内5～10℃)后，将双光气溶液慢慢滴入，确保尾气吸收装置中气泡不是太剧烈，滴加时间不少于2小时。滴加完后，向反应釜补加入三乙胺25mL，然后再滴加新的由双光气250g溶于400mL乙腈的溶液。
滴加完毕，搅拌保温8小时。保温结束，将反应釜反应液压入另外一台反应釜。开启反应釜导热油循环，升温到第二预设温度(釜内70～75℃)后，搅拌保温12小时。
反应完成后，自然降温后将反应液放出。在室温向反应液中慢慢通入氨气，调节pH值8左右。中和完毕，用压滤的方式除去固体杂质。静置1-2小时，蒸出溶剂，加水1000mL和500mL乙酸乙酯结晶得到三氯蔗糖-6-乙酸酯，将得到的产品情况列于表1。产率的计算方法为折纯后的三氯蔗糖-6-乙酸酯的质量比蔗糖-6-乙酸酯的质量，以下实施例算法相同。
实施例2
将实施例1中的尾气进行三级吸收，每级用400mL乙腈，吸收温度-10℃。分别用一级和二级吸收液分别溶解双光气350g，得到固体光气溶液两份。
采用上述两份固体光气溶液按照与实施例1相同的工艺制备三氯蔗糖-6-乙酸酯，结晶后三氯蔗糖-6-乙酸酯产品，将得到的产品情况列于表1。
实施例3
将已干燥好的200g原料蔗糖-6-乙酸酯(含量65.0wt％，DMF含量30wt％，含水量100ppm)放入至烧瓶中，开启搅拌，加入1000mL乙腈，升温至50℃加热溶解，约1小时。然后倒入5L反应釜，再向反应釜加入三乙胺25mL，充分搅拌溶解。
称量三光气250g加入圆底烧瓶中，加入400mL三氯乙烷，室温溶解完全。将三光气溶液倒入反应釜上的恒压滴液漏斗。开启冷媒循环，降温到第一预设温度(釜内5～10℃)后，将三光气溶液慢慢滴入，确保尾气吸收装置中气泡不是太剧烈，滴加时间不少于2小时。滴加完后，向反应釜补加入三乙胺25mL，然后再滴加新的由三光气250g溶于400mL三氯乙烷的溶液。
滴加完毕，搅拌保温6小时。保温结束，将反应釜反应液压入另外一台反应釜。开启反应釜导热油循环，升温到第二预设温度(釜内70～75℃)后，搅拌保温8小时。
反应完成后，自然降温后将反应液放出。在室温向反应液中慢慢通入氨气，调节pH值8左右。中和完毕，用压滤的方式除去固体杂质，静置1-2小时，蒸出溶剂，加水1000mL和500mL乙酸乙酯结晶得到三氯蔗糖-6-乙酸酯产品，将得到的产品情况列于表1。
实施例4
将已干燥好的200g原料蔗糖-6-乙酸酯(含量65.0wt％，DMF含量30wt％，含水量100ppm)放入至烧瓶中，开启搅拌，加入1000mL三氯乙烷，加热50℃溶解，约1小时，然后倒入5L反应釜。再向反应釜加入DMF 40mL，充分搅拌溶解。
称量三光气250g加入圆底烧瓶中，加入400mL三氯乙烷，室温溶解完全。将三光气溶液倒入反应釜上的恒压滴液漏斗。开启冷媒循环，降温到第一预设温度(釜内5～10℃)后，三光气溶液慢慢滴入，确保尾气吸收装置中气泡不是太剧烈，滴加时间不少于2小时。滴加完后，向反应釜补加入DMF 40mL，然后再滴加新的由三光气250g溶于400mL三氯乙烷的溶液。
滴加完毕，搅拌保温6小时。保温结束，将反应釜反应液压入另外一台反应釜。开启反应釜导热油循环，升温到第二预设温度(釜内105～115℃)后，搅拌保温4小时。
反应完成后，自然降温后将反应液放出。在室温向反应液中慢慢通入氨气，调节PH值8左右。中和完毕，用压滤的方式除去固体杂质。静置1-2小时，蒸出溶剂，加水1000mL和500mL乙酸乙酯结晶得到三氯蔗糖-6-乙酸酯产品，将得到的产品情况列于表1。
对比例1
在1000mL三口烧瓶内，将100g固体光气溶解于600g三氯乙烷中，冰盐水浴降温至-5℃，缓慢滴加75g DMF，控制温度不超过5℃，注意反应放热。最后得到乳自色液体。降温至0℃后开始缓慢滴加蔗糖-6-乙酸酯的DMF溶液150g(蔗糖-6-乙酸酯当量45g)，注意反应放热，控制温度小于5℃，滴加完毕后保温2小时，温度不超过5℃。
滴加完毕，搅拌保温6小时。保温结束，将反应釜反应液压入另外一台反应釜。开启反应釜导热油循环，升温到预定的反应温度(釜内105-115℃)后，搅拌保温4小时。
反应完成后，自然降温后将反应液放出。在室温向反应液中慢慢通入氨气，调节pH值8左右，中和完毕，用压滤的方式除去固体杂质。静置1-2小时，蒸出溶剂，加水400mL和200mL乙酸乙酯结晶得到三氯蔗糖-6-乙酸酯产品，将得到的产品情况列于表1。本对比例中，产率的计算方法为折纯后的三氯蔗糖-6-乙酸酯的质量比蔗糖当量。
对比例2
在1000mL三口烧瓶内，将100g固体光气溶解于600g三氯乙烷中，冰盐水浴降温至-5℃，缓慢滴加蔗糖-6-乙酸酯的DMF溶液35mL，控制温度不超过0℃，等待20分钟，出现小的结块，再等待5分钟，开始缓慢滴加蔗糖-6-乙酸酯的乙腈溶液，11分钟后结块消失。继续滴加蔗糖-6-乙酸酯的乙腈溶液140mL(蔗糖-6-乙酸酯当量42g)，注意反应放热，控制温度小于5℃，滴加完毕后保温2小时。
滴加完毕，搅拌保温6小时。保温结束，将反应釜反应液压入另外一台反应釜。 开启反应釜导热油循环，升温到预定的反应温度(釜内105-115℃)后，搅拌保温4小时。
反应完成后，自然降温后将反应液放出。在室温向反应液中慢慢通入氨气，调节pH值8左右，中和完毕，用压滤的方式除去固体杂质。静置1-2小时，蒸出溶剂，加水400mL和200mL乙酸乙酯结晶得到三氯蔗糖-6-乙酸酯产品15g，采用高效液相色谱测定其纯度为48％，折纯得三氯蔗糖-6-乙酸酯7.2g，产率18.00％，本对比例中，产率的计算方法为折纯后的三氯蔗糖-6-乙酸酯的质量比蔗糖当量。
表1 实施例1～4和对比例1～2产品情况列表
Figure PCTCN2020140221-appb-000001
从表1中可以看出，实施例1～4中制备的三氯蔗糖-6-乙酸酯的纯度均在60％以上，而对比例1和2均不能达到60％以上，实施例1～4中的产率也显著高于对比例1和对比例2。
从实施例2可以看出，本申请使用的溶剂经过简单处理即可进行回收使用，显著降低了成本，减少了废液的排放。
从实施例1～4和对比例1～2中可以看出，本发明使用固体光气替代传统的Vilsmeier试剂；一方面，避免了Vilsmeier试剂与DMF易结块的现状，且同时达到高效反应和减少污染的目的；另一方面，现有技术中使用的Vilsmeier试剂，如SOCl 2属剧毒液体，遇水反应剧烈，强烈腐蚀性，生产安全隐患较高。而本申请中使用的固体光气，更加方便运输和保存，并且生产过程中不存在蒸馏过程，安全可控性强，使得反应的安全性得到提升；再一方面，本申请环保方面优势更为明显， Vilsmeier试剂一般会产生大量的HCl和SO 2(SOCl 2制备法)，或者HCl和含磷废液(三氯化磷和三氯氧磷法制备法)，副产综合利用需要分离，工艺麻烦，或者高盐废水多。而本申请中固体光气工艺，转化率高，废气单纯，工艺废水少，好处理。
此外，本发明成本降低优势明显，每吨蔗糖-6-羧酸酯消耗固体光气约2.5吨，而使用Vilsmeier试剂，如SOCl 2或三氯氧磷，每吨蔗糖-6-羧酸酯消耗Vilsmeier试剂均在4吨以上，同时固体光气法收率会提高10％或以上，原料成本下降明显。因而采用本申请的方法会提高收率，减少消耗和三废，降低成本，非常适合于工业化生产。
以上所述，仅为本申请的具体实施方式，在本申请的上述教导下，本领域技术人员可以在上述实施例的基础上进行其他的改进或变形。本领域技术人员应该明白，上述的具体描述只是更好的解释本申请的目的，本申请的保护范围应以权利要求的保护范围为准。
此外，本领域的技术人员能够理解，尽管在此所述的一些实施例包括其它实施例中所包括的某些特征而不是其它特征，但是不同实施例的特征的组合意味着处于本申请的范围之内并且形成不同的实施例。例如，在下面的权利要求书中，所要求保护的实施例的任意之一都可以以任意的组合方式来使用。

Claims (10)

  1. 一种蔗糖-6-羧酸酯的氯代方法，其特征在于，包括：
    反应溶液制备步骤：将固体光气溶解在第一溶剂中而得到固体光气溶液，将蔗糖-6-羧酸酯溶解在第二溶剂中而得到羧酸酯溶液；
    反应物混合步骤：向所述羧酸酯溶液中加入催化剂，并搅拌至所述催化剂完全溶解，然后在第一预设温度下，向含有催化剂的羧酸酯溶液中缓慢滴加所述固体光气溶液；
    将所述反应物混合步骤操作多次，得到反应混合溶液；
    反应条件控制步骤：将所述反应混合溶液在第一预设温度下保持反应第一预设时间，然后升温至第二预设温度下保持反应第二预设时间使其进行氯代反应。
  2. 根据权利要求1所述的方法，其特征在于，还包括：
    后处理步骤：向所述反应混合溶液中加入pH值调节剂，调节pH值的范围在碱性预设范围。
  3. 根据权利要求2所述的方法，其特征在于，在所述后处理步骤中，所述向所述反应混合溶液中加入pH值调节剂，调节pH值的范围在碱性预设范围包括：
    将所述氯代反应得到的溶液降温到0～20℃，缓慢滴加氨水，调节pH值至7～9；
    或者，
    将所述氯代反应得到的溶液降温到30～50℃，缓慢通入氨气，调节pH值至7～9；
    或者，
    向所述氯代反应得到的溶液中缓慢滴加少量氨水，进行初步中和，然后通入氨气，调节pH值至7～9。
  4. 根据权利要求1所述的方法，其特征在于，在所述反应溶液制备步骤中，所述固体光气为氯甲酸三氯甲酯和/或双(三氯甲基)碳酸酯；
    以所述蔗糖-6-羧酸酯的质量用量为基准，所述固体光气的质量用量为蔗糖-6-羧酸酯的质量用量的1～8倍，优选2～4倍；
  5. 根据权利要求1所述的方法，其特征在于，所述第一溶剂为乙腈、三氯乙烷、二氯甲烷、二氯乙烷和三氯甲烷中的一种或几种，优选乙腈；
    所述固体光气溶液中所述固体光气的含量为5～50wt％，优选20～40wt％。
  6. 根据权利要求1所述的方法，其特征在于，在所述反应溶液制备步骤中，所述第二溶剂为乙腈、二氯甲烷、三氯乙烷、二氯乙烷和三氯甲烷中的一种，优选 乙腈和/或三氯乙烷；
    以所述蔗糖-6-羧酸酯的质量用量为基准，所述第二溶剂的体积用量为所述蔗糖-6-羧酸酯的质量用量的1～10倍，优选2～6倍。
  7. 根据权利要求1所述的方法，其特征在于，在所述反应物混合步骤中，所述催化剂为三乙胺、三甲胺、三苯胺、N，N-二甲基苯胺、N，N-二乙基苯胺、DMF或DMAC，优选三乙胺；
    以所述蔗糖-6-羧酸酯的质量用量为基准，所述催化剂的体积用量为所述蔗糖-6-羧酸酯的质量用量的0.01～0.5倍，优选0.1～0.4倍。
  8. 根据权利要求1所述的方法，其特征在于，在所述反应物混合步骤中，所述第一预设温度为0～25℃；所述催化剂与所述固体光气溶液的滴加总时长不少于1h；所述催化剂与所述固体光气溶液的滴加次数为2-10次。
  9. 根据权利要求1所述的方法，其特征在于，在所述反应条件控制步骤中，所述第一预设时间为1～24h，优选2～8h；
    所述第二预设温度为30～90℃，优选60～80℃；
    所述第二预设时间为2～48h，优选8～16h。
  10. 根据权利要求1～9中任一项所述的方法，其特征在于，所述蔗糖-6-羧酸酯是由蔗糖与有机锡化合物经过脱水反应，在于酸或酸酐经酰化反应制得，其中，所述有机锡化合物选自1,3-二(烃氧基)-1,1,3,3-四-(烃基)二锡氧烷、氧化二(烃基)锡、1,3-二酰氧基-1,1,3,3-四-(烃基)二锡氧烷和1-酰氧基-1,1,3,3-四-(烃基)二锡氧烷中的任意一种，优选1,3-二酰氧基-1,1,3,3-四-(烃基)二锡氧烷，最优选1,3-二乙酰氧基-1,1,3,3-四丁基二锡氧烷；所述有机锡化合物中的所述烃氧基为烷氧基或苯氧基，优选为甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基或正己氧基，更优选甲氧基；所述有机锡化合物中的烃基为烷基、环烷基、芳基或芳烷基，优选为烷基，更优选正丁基；
    所制得的蔗糖-6-羧酸酯在干燥前，其DMF含量为50wt％以下，优选30wt％以下；水含量低于0.1％，优选低于200ppm。
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