WO2022141228A1 - 三氯蔗糖的制备方法、粗产品溶液及三氯蔗糖 - Google Patents

三氯蔗糖的制备方法、粗产品溶液及三氯蔗糖 Download PDF

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WO2022141228A1
WO2022141228A1 PCT/CN2020/141528 CN2020141528W WO2022141228A1 WO 2022141228 A1 WO2022141228 A1 WO 2022141228A1 CN 2020141528 W CN2020141528 W CN 2020141528W WO 2022141228 A1 WO2022141228 A1 WO 2022141228A1
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sucralose
ethyl ester
reaction
solution
crude product
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PCT/CN2020/141528
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English (en)
French (fr)
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张正颂
赵金刚
钱庆喜
杨志健
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安徽金禾实业股份有限公司
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Priority to CN202080004024.8A priority Critical patent/CN112805291A/zh
Priority to PCT/CN2020/141528 priority patent/WO2022141228A1/zh
Publication of WO2022141228A1 publication Critical patent/WO2022141228A1/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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents
    • A23L27/33—Artificial sweetening agents containing sugars or derivatives
    • A23L27/37—Halogenated sugars
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention belongs to the technical field of fine chemicals, and particularly relates to a preparation method of sucralose, a crude product solution and sucralose.
  • Sucralose belongs to a new generation of sweeteners, which has the advantages of high sweetness, no calories, good stability and high safety, and has a very broad market prospect. Regarding the synthesis process of sucralose, great progress has been made since the advent of sucralose.
  • the mainstream synthesis process is the single-group protection method: the 6-position hydroxyl group with the highest activity of sucrose is selectively protected, usually in the form of ethyl ester, that is, to generate sucrose-6-ethyl ester, sucrose-6-ethyl ester
  • the three hydroxyl groups at the 4, 1' and 6' positions are selectively chlorinated to generate sucralose-6-ethyl ester, and the sucralose-6-ethyl ester is then deacetylated to generate sucralose.
  • the existing technology basically adopts a catalytic amount of sodium methoxide (MeONa) as a catalyst, and alcoholysis is carried out in methanol (MeOH) to remove the acetyl group to generate sucralose, and by-product methyl acetate etc. .
  • MeONa/MeOH catalytic system has the advantages of mild conditions, rapid reaction and high yield, but it also has certain disadvantages, such as MeONa is relatively expensive, and cannot be recycled, which increases production costs; removal of sodium ions requires the use of cationic resin, and the resin The regeneration will consume acid and alkali and produce a large amount of waste water.
  • sucralose-6-ethyl ester as the reaction raw material often contains a small amount of water
  • hydrolysis reaction as a side reaction, which competes with the main reaction of alcoholysis, which not only causes a large amount of waste of catalyst MeONa, but also generates sodium acetate.
  • the cationic resin is exchanged to generate acetic acid, and the acetic acid remains in the sucralose product, which makes the product have an obvious acidic odor, which seriously affects the product quality.
  • the present application is proposed to provide a method for preparing sucralose, a crude product solution and sucralose that overcome the above problems or at least partially solve the above problems.
  • a preparation method of sucralose comprising:
  • Dissolving step dissolving sucralose-6-ethyl ester in methanol to form a sucralose-6-ethyl ester reaction solution;
  • Catalysis step adding calcium oxide to the sucralose-6-ethyl ester reaction solution, and reacting under preset conditions, so that the sucralose-6-ethyl ester undergoes a deacylation reaction to form a sucralose mixed solution;
  • the step of removing impurities filtering the mixed solution of sucralose to obtain the crude product solution of sucralose.
  • a crude sucralose product solution prepared by the above-mentioned preparation method, wherein the acetic acid content is less than or equal to 230 ppm.
  • a sucralose is provided, which is obtained by crystallizing and refining the above-mentioned sucralose crude product solution.
  • the beneficial effects of the present application are: using calcium oxide as a catalyst, while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester, the calcium oxide can be removed and recycled by simple filtration, The catalyst consumption is reduced, and the production cost of sucralose is greatly reduced; in addition, calcium oxide can consume the water in the sucralose-6-ethyl ester, inhibit the occurrence of hydrolysis side reactions, and reduce the acetic acid in the final product. content, significantly improve product quality.
  • FIG. 1 shows a schematic flowchart of a method for preparing sucralose according to an embodiment of the present application.
  • MeONa/MeOH represents the coexistence of the two, specifically using MeONa as a catalyst and MeOH as a solvent
  • MeONa/MeOH represents the coexistence of the two, specifically using MeONa as a catalyst and MeOH as a solvent
  • the sucralose-6-ethyl ester as the reaction raw material often contains a small amount of water
  • the hydrolysis of the sucralose-6-ethyl ester will be caused, and the hydrolysis reaction will act as a
  • the side reaction competing with the main reaction of alcoholysis, will consume a large amount of catalyst MeONa and generate sodium acetate.
  • the sodium acetate is exchanged with an acidic cation resin to generate acetic acid. Due to the high boiling point of acetic acid, it is difficult to remove, and it is easy to remain in the final sucralose. In the product, the product has an obvious acidic odor, which seriously affects the quality of the product.
  • the hydrolysis reaction competes with the alcoholysis reaction, a large amount of catalyst is consumed, and the production cost of sucralose is increased.
  • the application uses calcium oxide as a catalyst, which can catalyze the deacetylation reaction efficiently and reliably, and the solubility of calcium oxide in the reaction system is very small, most of which can be removed and recycled through simple filtration, reducing Catalyst consumption, in addition, because calcium oxide will react with water very easily, consume the moisture present in the raw material, thereby avoiding the hydrolysis side reaction in the deacetylation process to generate acetic acid, so that there will be no acetic acid residue in the final sucralose product, The product quality is greatly improved, and the calcium hydroxide produced by the reaction of calcium oxide with water can also catalyze the deacetylation reaction.
  • Fig. 1 shows the schematic flow sheet of the preparation method of sucralose according to an embodiment of the present application, including:
  • Dissolving step S110 Dissolving sucralose-6-ethyl ester in methanol to form a sucralose-6-ethyl ester reaction solution.
  • sucralose-6-ethyl ester is dissolved in methanol, and sucralose-6-ethyl ester and methanol can be formed into a homogeneous mixture by means such as stirring.
  • Catalysis step S120 adding calcium oxide to the sucralose-6-ethyl ester reaction solution, and reacting under preset conditions, so that the sucralose-6-ethyl ester undergoes a deacylation reaction to form a sucralose mixed solution.
  • sucralose-6-ethyl ester the reaction process is shown in reaction formula (1).
  • the 6-position hydroxyl group has the highest activity of sucrose.
  • an acylating reagent such as acetic anhydride is used to protect it. Specifically, taking acetic anhydride as an example, Esterification of sucrose acetic anhydride is carried out to generate sucrose-6-ethyl ester. After the selective chlorination of the three hydroxyl groups at the 4, 1' and 6' positions, the deacylation reaction is carried out to finally generate sucralose, which is obtained by The protection of the 6-position hydroxyl group avoids the substitution of the 6-position hydroxyl group by a chlorine atom.
  • the present application mainly improves the step of deacetylation.
  • sodium methoxide is usually used as a catalyst and methanol is used as a solvent to carry out the deacetylation reaction. Since there is usually a small amount of water in the sucrose-6-ethyl ester solution, in the process of deacylation, a side reaction of hydrolysis will occur, which will compete with the main reaction of alcoholysis.
  • the reaction process is as shown in reaction formula (2) shown.
  • reaction formula (2) From the prior art shown in reaction formula (2), in the MeONa/MeOH catalytic system process, there is competition between the main reaction of alcoholysis and the side reaction of hydrolysis, and the hydrolysis reaction will consume the catalyst MeONa, and generate sodium acetate, and the sodium acetate is processed by The acid cation resin exchanges to produce acetic acid, which remains in the final product and affects the odor and taste of sucralose.
  • MeONa can be replaced by many different types of bases, which can be strong bases, weak bases, organic bases or inorganic bases, etc., and also include bases in immobilized forms such as basic anion resins. Both can catalyze the deacetylation process smoothly.
  • bases which can be strong bases, weak bases, organic bases or inorganic bases, etc., and also include bases in immobilized forms such as basic anion resins. Both can catalyze the deacetylation process smoothly.
  • the application uses calcium oxide as a catalyst.
  • calcium oxide can efficiently and reliably catalyze the deacylation reaction of sucralose-6-ethyl ester; on the other hand, calcium oxide reacts with water in sucralose-6-ethyl ester,
  • the generation of calcium hydroxide means that the side reaction of hydrolysis is suppressed, and the generated calcium hydroxide can also be used as a catalyst to catalyze the deacylation reaction of sucralose-6-ethyl ester.
  • the acyl group at the 6-position of sucralose-6-ethyl ester is removed to become a hydroxyl group, and the sucralose-6-ethyl ester is reduced to sucralose.
  • the impurity removal step S130 filtering the sucralose mixed solution to obtain a crude sucralose product solution.
  • the solubility of calcium oxide in the reaction system is very small. Therefore, the catalyst can be removed by filtering the three-filtered sucrose mixed solution obtained above.
  • the catalyst removal method in the present application is very simple, and only needs conventional means such as simple filtration. The process cost is greatly saved.
  • calcium oxide is used as a catalyst to efficiently and reliably catalyze the deacylation reaction of sucralose-6-ethyl ester.
  • calcium oxide can be removed and recycled through simple filtration, reducing catalyst consumption.
  • calcium oxide can consume the water in sucralose-6-ethyl ester, inhibit the occurrence of hydrolysis side reactions, reduce the content of acetic acid in the final product, significantly Improve product quality.
  • the step of removing impurities further includes: adding an acidic cationic resin to the sucralose mixed solution, and under the condition that the sucralose mixed solution is in a neutral condition , filtered to obtain a crude product solution of sucralose.
  • an acidic cationic resin can be added to it.
  • the acidic cationic resin can remove a small amount of calcium ions that may be dissolved in the system, and remove other possible impurities through adsorption. Filtration is carried out under neutral conditions, and the obtained filtrate is the crude product solution of sucralose with higher purity.
  • the above-mentioned preparation method of sucralose further comprises: a catalyst recovery step: recovering and reusing the catalyst obtained by filtering in the impurity removal step.
  • the catalyst will produce calcium hydroxide with a small amount of water in the first process. Therefore, most of the recovered catalyst is calcium oxide, including a small amount of calcium hydroxide, both of which can catalyze trichloride. Deacylation of sucrose-6-ethyl ester.
  • the above-mentioned preparation method of sucralose further comprises: a refining step of purifying and purifying the crude sucralose product solution to improve the purity of sucralose.
  • sucralose can be purified by adopting one or a combination of existing technologies.
  • the amount of methanol is not limited. In other embodiments, based on each gram of sucralose-6-ethyl ester, the amount of methanol is 3-10 mL by volume; if If the amount of methanol is less than 3mL by volume, the amount of methanol is insufficient, and the sucralose-6-ethyl ester cannot be completely dissolved; if the amount of methanol is greater than 10mL by volume, the amount of methanol is excessive, causing unnecessary waste. It cannot bring about other beneficial effects, and will increase the disposal amount of solvent removal in the subsequent sucralose crystallization process.
  • the amount of the catalyst is not limited.
  • the mass amount of calcium oxide is 0.5-1.0 grams per gram of sucralose-6-ethyl ester. If the amount of calcium oxide is less than 0.5g by mass, the amount of catalyst is too small, and it cannot rapidly catalyze the complete deacylation of sucralose-6-ethyl ester in a short time; if the amount of calcium oxide is greater than 1.0g by mass , the catalyst dosage is too much, causing unnecessary waste, and can not bring other beneficial effects, and the alkaline environment of the reaction solution is too strong, which may cause unnecessary side reactions.
  • the preset conditions are not limited, as long as the deacylation reaction can be achieved; in other embodiments, the preset conditions are: under stirring conditions, The reaction temperature was set to 10-60°C, and the reaction time was set to 0.5-24 h. Among them, stirring helps the reactant and the catalyst to mix uniformly, so that the reaction proceeds smoothly.
  • reaction temperature is less than 10°C and the reaction time is less than 0.5h, the reaction conditions are too mild, the time is too short, and the deacylation reaction cannot proceed completely; if the reaction temperature is higher than 60°C and the reaction time is longer than 6h, the reaction conditions are too intense, And if the time is too long, there is no obvious benefit, and it may cause unnecessary side effects.
  • Sucralose-6-ethyl ester can be obtained in the process of producing sucralose by using the existing single-group protection method, or a commercially available product can be used.
  • Reaction formula (3) shows the reaction process of the preparation method of sucralose according to another embodiment of the present application, as can be seen from reaction formula (3), sucralose-6-ethyl ester contains a small amount of water, Sucralose-6-ethyl ester is dissolved in methanol, and then calcium oxide is added as a catalyst for deacylation reaction. During this process, calcium oxide reacts with a small amount of water in sucralose-6-ethyl ester to form calcium hydroxide , calcium oxide and calcium hydroxide simultaneously catalyze the deacylation reaction of sucralose-6-ethyl ester to generate a mixed solution of sucralose.
  • test instruments and test conditions of the high performance liquid chromatography involved in this application are as follows:
  • high performance liquid chromatography can be used to determine the content of sucralose-6-ethyl ester, acetic acid and sucralose, which will not be repeated in each embodiment.
  • the judging criterion for the complete conversion of sucralose-6-ethyl ester is: sampling the reaction system, and in the high-performance liquid chromatography of the measured sample, excluding the solvent peak, it is displayed on the chromatogram. Among the remaining other species, the relative peak area of sucralose-6-ethyl ester was ⁇ 0.5%.
  • the reaction yield is: the percentage of the actual yield of sucralose measured by the external standard method of high performance liquid chromatography to the theoretical yield of the reaction.
  • the crude product solution of sucralose obtained by any of the above-mentioned methods can obtain a crude product with less acetic acid content compared to the prior art, and reduce or even avoid the negative impact of acetic acid.
  • the acetic acid content in the obtained crude product solution of sucralose is less than or equal to 230ppm, or even lower.
  • the obtained crude product solution of sucralose is purified by crystallization to obtain high-purity sucralose crystals. Crystallization can be achieved by one or a combination of methods in the prior art.
  • sucralose-6-ethyl ester In a three-necked round-bottomed flask with a volume of 1000 ml, add 100 g of sucralose-6-ethyl ester, add 300 ml of methanol, fully dissolve to form a homogeneous solution, and then add 5 g of calcium oxide to the solution. Equipped with a mechanical stirring device on the flask, turned on stirring, and maintained the reaction at 25° C. for 24 hours. The residual sucralose-6-ethyl ester was determined by high performance liquid chromatography ⁇ 0.5% (relative peak area), and the stirring was stopped.
  • the catalyst is removed by filtration, the obtained filtrate contains the crude sucralose product, and the acetic acid content in the filtrate measured by high performance liquid chromatography is below the detection limit, and further, the sucralose product can be further purified according to conventional methods, and the obtained sucralose There is no acidic odor in the finished product.
  • the yield of sucralose from the deacetylation reaction of sucralose-6-ethyl ester determined by high performance liquid chromatography was 85%.
  • the resin is removed by filtration, the obtained filtrate contains the crude sucralose product, and the acetic acid content in the filtrate measured by high performance liquid chromatography is below the detection limit. Further, the sucralose product can be further purified according to conventional methods, and the obtained sucralose There is no acidic odor in the finished product.
  • the yield of sucralose from the deacetylation of sucralose-6-ethyl ester was determined to be 88% by high performance liquid chromatography.
  • the catalyst is removed by filtration, the obtained filtrate contains the crude sucralose product, and the acetic acid content in the filtrate measured by high performance liquid chromatography is below the detection limit, and further, the sucralose product can be further purified according to conventional methods, and the obtained sucralose There is no acidic odor in the finished product.
  • the yield of sucralose by deacetylation of sucralose-6-ethyl ester determined by high performance liquid chromatography was 93%.
  • the sucralose product can be further purified according to conventional methods, and the obtained sucralose finished product has no acidic odor.
  • the yield of sucralose from the deacetylation reaction of sucralose-6-ethyl ester determined by high performance liquid chromatography was 90%.
  • Embodiment 5 (recovery catalyst is applied mechanically)
  • the sucralose product can be further purified according to conventional methods, and the obtained sucralose finished product has no acidic odor.
  • the yield of sucralose from the deacetylation of sucralose-6-ethyl ester was determined to be 88% by high performance liquid chromatography.
  • the resin is removed by filtration, the obtained filtrate contains the crude sucralose product, and the filtrate is determined by high performance liquid chromatography to contain acetic acid, and the content is 230ppm. Further, the sucralose product can be further purified according to conventional methods, and the gained sucralose finished product There is a distinct acidic odor.
  • the acid cation resin used needs to be washed and exchanged with acid and alkali for many times before it can be recycled.
  • the yield of sucralose from the deacetylation of sucralose-6-ethyl ester was determined to be 89% by high performance liquid chromatography.
  • the beneficial effects of the present application are: using calcium oxide as a catalyst, while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester, the calcium oxide can be removed and recycled by simple filtration, The catalyst consumption is reduced, and the production cost of sucralose is greatly reduced; in addition, calcium oxide can consume the water in the sucralose-6-ethyl ester, inhibit the occurrence of hydrolysis side reactions, and reduce the acetic acid in the final product. content, significantly improve product quality.

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Abstract

一种三氯蔗糖的制备方法、粗产品溶液及三氯蔗糖，该方法包括：将三氯蔗糖-6-乙酯溶于甲醇中，向三氯蔗糖-6-乙酯反应液中加入氧化钙进行脱酰基反应，过滤回收反应混合物中的氧化钙，得到三氯蔗糖粗产品溶液。

Description

三氯蔗糖的制备方法、粗产品溶液及三氯蔗糖 技术领域
本发明属于精细化工技术领域，具体涉及三氯蔗糖的制备方法、粗产品溶液及三氯蔗糖。
发明背景
三氯蔗糖属于新一代甜味剂，具有甜度高、无热量、稳定性好、安全性高等优点，市场前景非常广阔。关于三氯蔗糖的合成工艺，自三氯蔗糖问世以来，已有了长足的进步。目前为止，主流的合成工艺为单基团保护法：蔗糖活性最高的6位羟基被选择性保护，通常是以乙酯的形式，即生成蔗糖-6-乙酯，蔗糖-6-乙酯的4、1’、6’位的三个羟基再选择性进行氯代反应，生成三氯蔗糖-6-乙酯，三氯蔗糖-6-乙酯再脱去乙酰基，生成三氯蔗糖。
对于脱乙酰基步骤，现有工艺基本都采用催化量的甲醇钠(MeONa)为催化剂，在甲醇(MeOH)中进行醇解以脱去乙酰基，生成三氯蔗糖，及副产物乙酸甲酯等。采用MeONa/MeOH催化体系具有条件温和，反应迅速和产率高等优点，但是也有一定的缺点，如MeONa相对较昂贵，且不能回收利用，增加了生产成本；除去钠离子需要使用阳离子树脂,而且树脂的再生会消耗酸碱并产生大量废水等。
另外，由于作为反应原料的三氯蔗糖-6-乙酯中往往含有少量水分，存在水解反应作为副反应，与醇解主反应竞争，不但造成催化剂MeONa大量浪费，而且会生成醋酸钠，经酸性阳离子树脂交换生成醋酸，醋酸残留在三氯蔗糖产品中，使得产品有明显的酸性气味，严重影响产品品质。
因此，从三氯蔗糖-6-乙酯脱去酰基合成三氯蔗糖的工艺还有很大的改善和提升空间。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三氯蔗糖的制备方法、粗产品溶液及三氯蔗糖。
根据本申请的一方面，提供了一种三氯蔗糖的制备方法，包括：
溶解步骤：将三氯蔗糖-6-乙酯溶于甲醇中，形成三氯蔗糖-6-乙酯反应液；
催化步骤：向三氯蔗糖-6-乙酯反应液中加入氧化钙，在预设条件下反应，以使三氯蔗糖-6-乙酯发生脱酰基反应，形成三氯蔗糖混合溶液；
除杂步骤：对三氯蔗糖混合溶液进行过滤，得到三氯蔗糖粗产品溶液。
根据本申请的另一方面，提供了一种三氯蔗糖粗产品溶液，其是采用上述的制备方法制得的，其中乙酸含量≤230ppm。
根据本申请的再一方面，提供了一种三氯蔗糖，其是采用上述的三氯蔗糖粗产品溶液结晶精制而得。
综上所述，本申请的有益效果在于：采用氧化钙作为催化剂，在高效可靠地催化三氯蔗糖-6-乙酯脱酰基化反应的同时，氧化钙通过简单过滤即可去除并回收利用，降低了催化剂消耗量，很大程度上降低了三氯蔗糖的生产成本；另外由于氧化钙能够消耗掉三氯蔗糖-6-乙酯中的水分，抑制水解副反应的发生，降低最终产物中乙酸的含量，显著提高产品品质。
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。
附图简要说明
通过阅读下文优选实施方式的详细描述，各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的，而并不认为是对本申请的限制。而且在整个附图中，用相同的参考符号表示相同的部件。在附图中：
图1示出了根据本申请一个实施例的三氯蔗糖的制备方法的流程示意图。
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。
尽管MeONa/MeOH(MeONa/MeOH代表二者同时存在，具体以MeONa作为 催化剂，MeOH为溶剂)体系作为经典组合，用于糖类物质脱乙酰基(即Zemplén反应)应用广泛，但是MeONa/MeOH体系作为催化剂存在着很多弊端，例如，由于作为反应原料的三氯蔗糖-6-乙酯中往往含有少量水分，在MeONa的存在下，会导致三氯蔗糖-6-乙酯的水解，水解反应作为副反应，与醇解的主反应竞争，会大量消耗催化剂MeONa，生成醋酸钠，醋酸钠经酸性阳离子树脂交换生成醋酸，由于醋酸沸点高，导致其很难除去，容易残留在最终的三氯蔗糖产品中，使得产品有明显的酸性气味，严重影响产品品质。且由于水解反应与醇解反应竞争，消耗掉大量催化剂，增加三氯蔗糖生产成本。
针对上述问题，本申请采用氧化钙作为催化剂，氧化钙能够高效可靠地催化脱乙酰基反应，且氧化钙在反应体系中溶解度非常小，大部分可以通过简单过滤即可去除并回收利用，降低了催化剂消耗量，另外由于氧化钙会非常容易地与水反应，消耗原料中存在的水分，从而避免脱乙酰基过程中水解副反应产生醋酸，使得最终的三氯蔗糖产品中不会有醋酸残留，极大地提升产品品质，并且氧化钙与水反应生成的氢氧化钙也可以催化脱乙酰基反应。
图1示出了根据本申请一个实施例的三氯蔗糖的制备方法的流程示意图，包括：
溶解步骤S110：将三氯蔗糖-6-乙酯溶于甲醇中，形成三氯蔗糖-6-乙酯反应液。
首先，将三氯蔗糖-6-乙酯溶解于甲醇中，可以通过搅拌等手段，使得三氯蔗糖-6-乙酯与甲醇形成均相混合物。
催化步骤S120：向三氯蔗糖-6-乙酯反应液中加入氧化钙，在预设条件下反应，以使三氯蔗糖-6-乙酯发生脱酰基反应，形成三氯蔗糖混合溶液。
目前制备三氯蔗糖应用最广泛的方式是单基团保护法，以三氯蔗糖-6-乙酯为例，其反应过程如反应式(1)所示。
反应式(1)
Figure PCTCN2020141528-appb-000001
从反应式(1)中，可以看出，蔗糖活性最高的是6位羟基，在单基团保护法中，采用乙酸酐等酰基化试剂将其保护起来，具体的，以乙酸酐为例，将蔗糖乙酸酐进行酯化反应，生成蔗糖-6-乙酯，在4、1’、6’位的三个羟基完成选择性氯代反应后，进行脱酰基反应，最终生成三氯蔗糖，通过对6位羟基的保护，避免6位上的羟基被氯原子取代。
本申请主要是针对脱乙酰基这一步进行了改进，在现有技术中，通常采甲醇钠作为催化剂，甲醇作为溶剂进行脱乙酰基反应。由于通常在蔗糖-6-乙酯溶液中存在着少量的水分，因此，在脱酰基的过程中，会发生水解副反应，其与醇解主反应会发生竞争，反应过程如反应式(2)所示。
反应式(2)
Figure PCTCN2020141528-appb-000002
从反应式(2)示出的现有技术中采用MeONa/MeOH催化体系工艺中，醇解主反应和水解副反应之间存在竞争，水解反应会消耗催化剂MeONa，并生成醋酸钠，醋酸钠经酸性阳离子树脂交换生成醋酸，醋酸残留到最终产品中，影响三氯蔗糖的气味和口感。
针对上述情况，在Zemplén反应体系中，MeONa可以为许多种不同类型的碱所替代，可以是强碱、弱碱、有机碱或无机碱等，也包括碱性阴离子树脂等固载形 式的碱，都可以很顺利地催化脱乙酰基过程。本申请采用氧化钙作为催化剂，一方面，氧化钙能够高效可靠地催化三氯蔗糖-6-乙酯脱酰基反应；另一方面，氧化钙与三氯蔗糖-6-乙酯中的水反应，生成氢氧化钙，即抑制了水解副反应，生成的氢氧化钙也可以作为催化剂，催化三氯蔗糖-6-乙酯脱酰基反应。
经过催化步骤，三氯蔗糖-6-乙酯的6位上的酰基发生脱除，变成羟基，三氯蔗糖-6-乙酯被还原为三氯蔗糖。
以及除杂步骤S130：对三氯蔗糖混合溶液进行过滤，得到三氯蔗糖粗产品溶液。
氧化钙在反应体系中的溶解度非常小，因此，对上述得到的三滤蔗糖混合溶液进行过滤，即可去除催化剂，本申请中去除催化剂方法非常简单，仅需简单的过滤等常规手段即可，极大的节约了工艺成本。
由图1所示的方法，采用氧化钙作为催化剂，在高效可靠地催化三氯蔗糖-6-乙酯脱酰基化反应的同时，氧化钙通过简单过滤即可去除并回收利用，降低了催化剂消耗量，极大程度上降低了三氯蔗糖的生产成本；另外由于氧化钙能够消耗掉三氯蔗糖-6-乙酯中的水分，抑制水解副反应的发生，降低最终产物中乙酸的含量，显著提高产品品质。
在本申请的一些实施例中，在上述的三氯蔗糖的制备方法中，除杂步骤还包括：向三氯蔗糖混合溶液中加入酸性阳离子树脂，在三氯蔗糖混合溶液处于中性的条件下，进行过滤，得到三氯蔗糖粗产品溶液。
为了得到进一步的纯化三氯蔗糖粗产品溶液，可向其中加入酸性阳离子树脂，酸性阳离子树脂能够除去体系中可能溶解的少量的钙离子，以及通过吸附作用，除去其它可能存在的杂质，进而在体系处于中性条件下进行过滤，得到的滤液即为纯度更高的三氯蔗糖粗产品溶液。
另需说明的是，这里说的中性条件不是严格意义的pH＝7的条件，在pH＝6-8这一范围内，均可认为三氯蔗糖混合溶液已达到中性的条件。
在本申请的一些实施例中，上述的三氯蔗糖的制备方法还包括：催化剂回收步骤：对除杂步骤中经过滤得到的催化剂回收复用。
本申请中催化剂在第一次的过程中会有少量与水生产氢氧化钙，因此，回收的催化剂中绝大部分为氧化钙，其中还包括少量的氢氧化钙，二者均可可催化三氯蔗糖-6-乙酯脱酰基反应。
在本申请的一些实施例中，上述的三氯蔗糖的制备方法还包括：精制步骤，对三氯蔗糖粗产品溶液进行提纯精制，以提高三氯蔗糖纯度。
为了进一步提高三氯蔗糖的纯度，可采用现有技术中的一种或几种的结合对三氯蔗糖进行提纯。
药品的来源
在本申请中，如不作特殊说明，常规药品均可采用市售产品，不一一赘述。
甲醇的用量和来源
在本申请的一些实施例中，对甲醇的用量不做限定，在另外一些实施例中，以每克三氯蔗糖-6-乙酯为基准，甲醇的用量以体积计为3～10mL；若甲醇的用量以体积计小于3mL，则甲醇的用量不足，不能完全溶解三氯蔗糖-6-乙酯；若甲醇的用量以体积计大于10mL，则甲醇的用量过量，造成不必要的浪费，并不能带来其他有益效果，而且会增加了后续三氯蔗糖结晶工艺的去除溶剂的处置量。
氧化钙的用量
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，以每克三氯蔗糖-6-乙酯为基准，氧化钙的质量用量为0.5～1.0克。若氧化钙的用量以质量计小于0.5g，则催化剂用量过少，不能够在短时间内快速催化三氯蔗糖-6-乙酯完全脱酰基化；若氧化钙的用量以质量计大于1.0g，则催化剂用量过多，造成不必要的浪费，并不能带来其他有益效果，而且反应液碱性环境过强，可能引起不必要的副反应。
预设条件
在本申请的一些实施例中，在所述催化步骤中，对预设条件不做限定，凡是可实现脱酰基反应即可；在另一些实施例中，预设条件为：搅拌的条件下，反应温度设为10～60℃，反应时间设为0.5～24h。其中，搅拌有助于反应物与催化剂反应混合均匀，使得反应顺利进行。若反应温度小于10℃，反应时间若小于0.5h，则反应条件过于温和，时间过短，脱酰基反应不能完全进行；若反应温度大于60℃，反应时间若大于6h，则反应条件过于激烈，且时间过长，没有明显的益处，且可能引起不必要的副反应。
三氯蔗糖-6-乙酯的来源
三氯蔗糖-6-乙酯可为采用现有的单基团保护法生产三氯蔗糖的过程中得来，也可以采用市售产品。
反应式(3)示出了根据本申请另一个实施例的三氯蔗糖的制备方法的反应过程，由反应式(3)可以看出，三氯蔗糖-6-乙酯中含有少量的水，将三氯蔗糖-6-乙酯溶于甲醇，然后加入氧化钙作为催化剂进行脱酰基反应，在这个过程中，氧化钙与三氯蔗糖-6-乙酯中少量的水反应，生成氢氧化钙，氧化钙与氢氧化钙同时催化三氯蔗糖-6-乙酯脱酰基反应，生成三氯蔗糖混合溶液。
反应式(3)
Figure PCTCN2020141528-appb-000003
测定手段
本申请中涉及的高效液相色谱法的测试仪器和测试条件如下所示：
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、其他标准物质，外标法测量含量。
在本申请中，高效液相色谱法可用来测定三氯蔗糖-6-乙酯、醋酸和三氯蔗糖的含量，在各个实施例中不再赘述。
水含量的测定使用卡尔费休法，请参考现有技术，在各个实施例中不再赘述。
产率的计算方法：
各实施例和对比例中，三氯蔗糖-6-乙酯完全转化完毕的判断标准为：对反应体系取样，对所取样品测定的高效液相色谱中，不计溶剂峰，在色谱图上显示的剩余其它物种中，三氯蔗糖-6-乙酯的相对峰面积≤0.5％。
反应产率为：以高效液相色谱外标法测定得到的三氯蔗糖实际产量占反应理论产量的百分比。
通过上述任一的方法得到的三氯蔗糖的粗产品溶液，且相对于现有技术能够得到乙酸含量更少的粗产品，降低甚至避免乙酸带来的负面影响，在本申请的一些实施例中，得到的三氯蔗糖的粗产品溶液中乙酸含量≤230ppm，甚至更低。
通过上对得到的三氯蔗糖的粗产品溶液通过结晶精制得到高纯度的三氯蔗糖晶体。结晶精制可通过现有技术中一种或几种方法的结合实现。
实施例1
在一容积为1000毫升的三口圆底烧瓶中，加入100克三氯蔗糖-6-乙酯，加入300毫升甲醇，充分溶解，形成均相溶液，再向溶液中加入5克氧化钙。在烧瓶上装备机械搅拌装置，开启搅拌，维持25℃反应24小时后，高效液相色谱测定三氯蔗糖-6-乙酯剩余≤0.5％(相对峰面积)，停止搅拌。过滤除去催化剂，所得滤液中含有三氯蔗糖粗产品，且高效液相色谱测定滤液中醋酸含量在检测限以下，进一步地，可以按照常规方法对三氯蔗糖产品进行进一步的提纯，所得三氯蔗糖成品中没有酸性气味。高效液相色谱测定三氯蔗糖-6-乙酯脱乙酰基反应生成三氯蔗糖的产率为85％。
实施例2
在一容积为1000毫升的三口圆底烧瓶中，加入100克三氯蔗糖-6-乙酯，加入500毫升甲醇，充分溶解，形成均相溶液，再向溶液中加入20克氧化钙。在烧瓶上装备机械搅拌装置，开启搅拌，维持40℃反应6小时后，高效液相色谱显示三氯蔗糖-6-乙酯剩余≤0.5％(相对峰面积)，停止搅拌。过滤除去树脂，所得滤液中含有三氯蔗糖粗产品，且高效液相色谱测定滤液中醋酸含量在检测限以下，进一步地，可以按照常规方法对三氯蔗糖产品进行进一步的提纯，所得三氯蔗糖成品中没有酸性气味。高效液相色谱测定三氯蔗糖-6-乙酯脱乙酰基反应生成三氯蔗糖的产率为88％。
实施例3
在一容积为1000毫升的三口圆底烧瓶中，加入100克三氯蔗糖-6-乙酯，加入500毫升甲醇，充分溶解，形成均相溶液，再向溶液中加入50克氧化钙。在烧瓶上装备机械搅拌装置，维持25℃反应2小时后，高效液相色谱显示三氯蔗糖-6-乙 酯剩余≤0.5％(相对峰面积)，停止搅拌。过滤除去催化剂，所得滤液中含有三氯蔗糖粗产品，且高效液相色谱测定滤液中醋酸含量在检测限以下，进一步地，可以按照常规方法对三氯蔗糖产品进行进一步的提纯，所得三氯蔗糖成品中没有酸性气味。高效液相色谱测定三氯蔗糖-6-乙酯脱乙酰基反应生成三氯蔗糖的产率为93％。
实施例4
在一容积为2000毫升的三口圆底烧瓶中，加入100克三氯蔗糖-6-乙酯，加入1000毫升甲醇，充分溶解，形成均相溶液，再向溶液中加入100克氧化钙。在烧瓶上装备机械搅拌装置，开启搅拌，维持60℃反应1小时后，高效液相色谱显示三氯蔗糖-6-乙酯剩余≤0.5％(相对峰面积)，停止搅拌。过滤除去催化剂，再使用少量酸性阳离子树脂调节反应液为中性后，过滤除去树脂，所得滤液中含有三氯蔗糖粗产品，且高效液相色谱测定滤液中醋酸含量在检测限以下，进一步地，可以按照常规方法对三氯蔗糖产品进行进一步的提纯，所得三氯蔗糖成品中没有酸性气味。高效液相色谱测定三氯蔗糖-6-乙酯脱乙酰基反应生成三氯蔗糖的产率为90％。
实施例5(回收催化剂套用)
在一容积为2000毫升的三口圆底烧瓶中，加入100克三氯蔗糖-6-乙酯，加入1000毫升甲醇，充分溶解，形成均相溶液，再向溶液中加入实施例4中回收的催化剂。在烧瓶上装备机械搅拌装置，开启搅拌，维持60℃反应2小时后，高效液相色谱显示三氯蔗糖-6-乙酯剩余≤0.5％(相对峰面积)，停止搅拌。过滤除去催化剂，再使用少量酸性阳离子树脂调节反应液为中性后，过滤除去树脂，所得滤液中含有三氯蔗糖粗产品，且高效液相色谱测定滤液中醋酸含量在检测限以下，进一步地，可以按照常规方法对三氯蔗糖产品进行进一步的提纯，所得三氯蔗糖成品中没有酸性气味。高效液相色谱测定三氯蔗糖-6-乙酯脱乙酰基反应生成三氯蔗糖的产率为88％。
对比例1(MeONa/MeOH体系脱乙酰基)
在一容积为1000毫升的三口圆底烧瓶中，加入100克三氯蔗糖-6-乙酯，加入300毫升甲醇，充分溶解，形成均相溶液，再向溶液中加入2克甲醇钠。在烧瓶上装备机械搅拌装置，开启搅拌，维持25℃反应6小时后，高效液相色谱测定三氯 蔗糖-6-乙酯剩余≤0.5％(相对峰面积)，停止搅拌。向反应液中加入适量酸性阳离子树脂，维持低速搅拌，直至反应液pH为7。过滤除去树脂，所得滤液中含有三氯蔗糖粗产品，高效液相色谱测定滤液中含有醋酸，含量为230ppm，进一步地，可以按照常规方法对三氯蔗糖产品进行进一步的提纯，所得三氯蔗糖成品中有明显酸性气味。所使用的酸性阳离子树脂需要使用酸和碱等多次淋洗交换处理后，才可回收使用。高效液相色谱测定三氯蔗糖-6-乙酯脱乙酰基反应生成三氯蔗糖的产率为89％。
从实施例1～5和对比例1可以看出，采用本申请的方法，采用氧化钙作为催化剂，氧化钙通过化学反应将三氯蔗糖-6-乙酯中的水分消耗掉，生成氢氧化钙，抑制了水解副反应，使得产物中醋酸含量极低，所得三氯蔗糖成品中没有酸性气味，且在催化剂通过简单过滤即可回收复用，极大程度上降低了三滤蔗糖的生成成本。
综上所述，本申请的有益效果在于：采用氧化钙作为催化剂，在高效可靠地催化三氯蔗糖-6-乙酯脱酰基化反应的同时，氧化钙通过简单过滤即可去除并回收利用，降低了催化剂消耗量，极大程度上降低了三氯蔗糖的生产成本；另外由于氧化钙能够消耗掉三氯蔗糖-6-乙酯中的水分，抑制水解副反应的发生，降低最终产物中乙酸的含量，显著提高产品品质。
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. 一种三氯蔗糖的制备方法，其特征在于，包括：
    溶解步骤：将三氯蔗糖-6-乙酯溶于甲醇中，形成三氯蔗糖-6-乙酯反应液；
    催化步骤：向所述三氯蔗糖-6-乙酯反应液中加入氧化钙，在预设条件下反应，以使所述三氯蔗糖-6-乙酯发生脱酰基反应，形成三氯蔗糖混合溶液；以及
    除杂步骤：对所述三氯蔗糖混合溶液进行过滤，得到三氯蔗糖粗产品溶液。
  2. 根据权利要求1所述的方法，其特征在于，所述除杂步骤还包括：
    向所述三氯蔗糖混合溶液中加入酸性阳离子树脂，在所述三氯蔗糖混合溶液处于中性的条件下，进行过滤，得到三氯蔗糖粗产品溶液。
  3. 根据权利要求1所述的方法，其特征在于，还包括：
    催化剂回收步骤：对所述除杂步骤中经过滤得到的催化剂回收复用。
  4. 根据权利要求1所述的方法，其特征在于，还包括：
    精制步骤，对所述三氯蔗糖粗产品溶液进行提纯精制，以提高三氯蔗糖纯度。
  5. 根据权利要求1所述的方法，其特征在于，以每克三氯蔗糖-6-乙酯为基准，所述甲醇的用量以体积计为3～10mL。
  6. 根据权利要求1所述的方法，其特征在于，以每克三氯蔗糖-6-乙酯为基准，所述氧化钙的用量以质量计为0.5～1.0克。
  7. 根据权利要求1所述的方法，其特征在于，在所述催化步骤中，所述预设条件为：搅拌的条件下，反应温度设为10～60℃，反应时间设为0.5～24h。
  8. 根据权利要求1所述的方法，其特征在于，还包括：
    结晶步骤：对所述三氯蔗糖粗产品溶液进行结晶提纯，得到三氯蔗糖晶体。
  9. 一种三氯蔗糖粗产品溶液，其是采用权利要求1～7中任一项所述的方法制得的，其副产品乙酸含量≤230ppm。
  10. 一种三氯蔗糖，其是采用权利要求9中的三氯蔗糖粗产品溶液结晶精制而得。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2012CH03430A (zh) * 2012-08-21 2012-09-28 Divi's Laboratories Ltd
CN104098615A (zh) * 2014-06-09 2014-10-15 华中科技大学 一种以氢氧根离子型的碱为催化剂进行脱酰基化的方法
CN105859802A (zh) * 2016-05-14 2016-08-17 广西科技大学 一种三氯蔗糖的结晶和纯化方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2012CH03430A (zh) * 2012-08-21 2012-09-28 Divi's Laboratories Ltd
CN104098615A (zh) * 2014-06-09 2014-10-15 华中科技大学 一种以氢氧根离子型的碱为催化剂进行脱酰基化的方法
CN105859802A (zh) * 2016-05-14 2016-08-17 广西科技大学 一种三氯蔗糖的结晶和纯化方法

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