WO2022099606A1 - 三氯蔗糖的提纯方法 - Google Patents

三氯蔗糖的提纯方法 Download PDF

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WO2022099606A1
WO2022099606A1 PCT/CN2020/128654 CN2020128654W WO2022099606A1 WO 2022099606 A1 WO2022099606 A1 WO 2022099606A1 CN 2020128654 W CN2020128654 W CN 2020128654W WO 2022099606 A1 WO2022099606 A1 WO 2022099606A1
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sucralose
temperature
ethyl acetate
crude product
crystals
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PCT/CN2020/128654
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English (en)
French (fr)
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李正华
夏家信
许传久
徐国家
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安徽金禾实业股份有限公司
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Priority to CN202080004013.XA priority Critical patent/CN112585151A/zh
Priority to MX2023005617A priority patent/MX2023005617A/es
Priority to EP20961162.3A priority patent/EP4215538A4/en
Priority to US18/250,728 priority patent/US20230399351A1/en
Priority to PCT/CN2020/128654 priority patent/WO2022099606A1/zh
Publication of WO2022099606A1 publication Critical patent/WO2022099606A1/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
    • C07H1/06—Separation; Purification
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0018—Evaporation of components of the mixture to be separated
    • B01D9/0031—Evaporation of components of the mixture to be separated by heating
    • 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    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0488—Flow sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0492—Applications, solvents used
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0004—Crystallisation cooling by heat exchange
    • B01D9/0013—Crystallisation cooling by heat exchange by indirect heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0059—General arrangements of crystallisation plant, e.g. flow sheets

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  • the application belongs to the field of fine chemical manufacturing, and in particular relates to a method for purifying 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 single-group protection (as shown in Figure 1), that is, the 6-position hydroxyl group with the highest activity of sucrose is selectively protected, usually in the form of acetate, that is, to generate sucrose-6- Ethyl ester, the three hydroxyl groups at the 4, 1', 6' positions of sucralose-6-ethyl ester are selectively chlorinated to generate sucralose-6-ethyl ester, and the sucralose-6-ethyl ester is then removed. After deacetylation, sucralose was finally synthesized.
  • the purification of sucralose mainly adopts a large amount of butyl acetate as the extraction solvent to extract the aqueous solution of the crude sucralose product, which has the defects of large amount of solvent and a large amount of organic waste liquid;
  • the high boiling point of butyl acetate leads to higher energy consumption in the subsequent removal process, and the use of butyl acetate increases the types of materials to be operated in the process system. All of these increase the production cost and are not conducive to clean production, so there is still a lot of room for improvement of the sucralose purification process.
  • a method for purifying sucralose comprising:
  • Concentration step remove the solvent from the sucralose reaction solution to obtain a concentrated solution of the sucralose crude product
  • Beating step under stirring, add ethyl acetate to the concentrated solution of the crude sucralose product, heat to a preset temperature, and keep it for a first preset time to obtain a crude product slurry containing part of the sucralose crystals ;
  • a sucralose prepared by the above method and the HPLC purity of the prepared sucralose is ⁇ 97%.
  • the beneficial effects of the present application are: compared with the existing widely used butyl acetate extraction process, a direct beating treatment of the concentrate of the crude sucralose product is proposed, without the need to redissolve the crude sucralose product
  • the method for purifying into a solution the method for purifying sucralose of the present application has the advantages of simple operation, small disposal capacity, few required solvent amounts, etc.; Therefore, the use of ethyl acetate will not increase the extra species in the technological process, and the boiling point of ethyl acetate is much lower than that of butyl acetate, which greatly reduces the energy consumption in the process of distillation and recovery, which is beneficial to Improve production efficiency and reduce production costs.
  • Fig. 1 shows the process flow schematic diagram of sucralose monogene protection method in the prior art
  • Fig. 2 shows a kind of process flow schematic diagram of adopting butyl acetate to extract sucralose in the prior art
  • Fig. 3 shows the process flow schematic diagram of the purification method of sucralose according to an embodiment of the present application
  • Fig. 4 shows the high performance liquid chromatogram of sucralose crude product reaction solution
  • Example 5 is a high performance liquid chromatogram of sucralose treated by the method of Example 1.
  • the inventive concept of the present application is: due to the high polarity of sucralose, the solubility in water is much greater than that in ethyl acetate, and in the crude sucralose product obtained by the deacetylation reaction, there are many impurities. It is a species with small polarity.
  • the present application finds that using ethyl acetate for beating the crude sucralose product can selectively remove various impurities and achieve a good purification effect.
  • Figure 2 shows a schematic diagram of the process flow of the prior art using butyl acetate to extract sucralose, as shown in Figure 2, firstly, the deacetylation reaction solution containing the crude sucralose product is concentrated to remove the solvent, and then Then add water to dissolve to form an aqueous solution of the crude sucralose product, and then extract the aqueous solution with butyl acetate to remove impurities, and then purify the impurity-removed aqueous solution. of sucralose. Due to the need to use high-boiling butyl acetate, there are disadvantages such as large amount of solvent, high energy consumption, and increased consumption of raw material species.
  • Fig. 3 shows the process flow schematic diagram of the purification method of sucralose according to an embodiment of the present application, and the purification method of this sucralose comprises:
  • Concentration step the solvent is removed from the sucralose reaction solution to obtain a concentrated solution of the crude sucralose product.
  • the method for purifying sucralose provided by the present application is carried out for the mixed solution containing the crude sucralose product generated after the deacetylation reaction of sucralose-6 acetate in the preparation process of sucralose,
  • the purpose is to use certain technical means to purify sucralose from the mixed solution containing the crude sucralose product.
  • the mixed solution containing the crude sucralose product is called the sucralose reaction solution.
  • the method for purifying sucralose provided by the present application firstly removes a large amount of organic solvent in the sucralose reaction solution, and the removal method adopts conventional means in the field.
  • a concentrated solution containing the crude sucralose product is obtained, which is called the concentrated solution of the crude sucralose product.
  • Beating step under stirring conditions, add ethyl acetate to the concentrated solution of the crude sucralose product, heat it to a preset temperature, and keep it for a period of time, recorded as the first preset time, to obtain a part of the sucralose crystals. Crude product slurry.
  • ethyl acetate is added directly to the concentrated solution of the crude sucralose product, and under preset conditions, the Sucralose crude product concentrated solution beating.
  • a variety of organic impurities with small polarity in the sucralose reaction solution will enter into ethyl acetate, and then through the subsequent steps, the ethyl acetate mother liquor containing impurities is filtered and removed, so as to achieve the removal of the sucralose reaction solution. the purpose of impurities.
  • the purpose of this collection step is to promote complete precipitation of sucralose crystals by cooling. After the beating is completed, it is not necessary to separate ethyl acetate from the sucralose reaction solution, but the crude product slurry containing part of the sucralose crystals is directly subjected to gradient cooling, so that the unprecipitated sucralose is removed from the reaction solution.
  • the above-mentioned method for purifying sucralose may further include a refining step: further refining the obtained sucralose to obtain refined sucralose crystals.
  • the obtained sucralose can be further refined.
  • the obtained sucralose is recrystallized to obtain sucralose with a further improved purity. sucrose.
  • This embodiment recommends a method for recrystallization of sucralose, including: a dissolving step: putting sucralose into deionized water for heating and dissolving, decolorizing with activated carbon, and filtering to obtain a recrystallization solution; concentration step: dissolving the recrystallization solution Evaporating and concentrating to a preset concentration; crystal nucleation step: leaving the concentrated recrystallization solution at a preset temperature for a period of time to form sucralose crystal nuclei; Gradient cooling to obtain a recrystallization solution containing a large number of sucralose crystals; filtering step: centrifuging, washing and drying the recrystallization solution containing a large number of sucralose crystals to obtain sucralose crystals.
  • the amount of ethyl acetate is not limited.
  • the volume of ethyl acetate is 0.2-0.5 mL based on the concentrated solution of each gram of sucralose crude product. If the volumetric dosage of ethyl acetate is less than 0.2 mL/1 g of the crude sucralose product solution, the dosage is too small to completely extract the organic impurities in the sucralose reaction solution; if the volumetric dosage of ethyl acetate More than 0.5mL/1 gram of sucralose crude product solution, then the dosage is too much, on the one hand, it causes unnecessary waste of ethyl acetate, and on the other hand, the concentration of sucralose crude product slurry is too low, which is not conducive to sucralose. Subsequent crystallization even causes problems such as incomplete crystallization, complex and diverse crystal forms, and low yield of the generated sucralose.
  • the preset temperature in the beating step is not limited. In some embodiments, the preset temperature is 45°C to 65°C. If the preset temperature is lower than 45°C, the beating temperature is too low, and the ethyl acetate cannot be well mixed with the concentrated solution of the crude sucralose product; if the preset temperature is higher than 65°C, the beating temperature is too high, which is easy to cause The concentrated solution of the crude sucralose product is partially overheated, or even boiled, and the ethyl acetate is ineffectively volatilized.
  • the first preset time in the first beating step that is, the beating time is not limited, and in some embodiments, the first preset time is 0.5h-3h. If the first preset time is shorter than 0.5h, the beating time is too short, that is, the extraction time is too short, and various organic impurities cannot completely enter the ethyl acetate; if the first preset time is higher than 3h, the beating time is too long , that is, the extraction time is too long, causing the overall purification process time to be too long, and can not bring other beneficial effects.
  • the purpose of the gradient cooling process in the collection step is to promote the rapid and massive precipitation of unprecipitated sucralose crystals.
  • the present application does not limit the gradient cooling process in the collection step.
  • the gradient cooling is to cool down to the temperature end point at a speed of 1-3°C/10min; the temperature end point is 0-10°C.
  • gradient cooling can be used to precipitate a large amount of sucralose crystals.
  • the gradient cooling is to lower the temperature to 0-10°C at a rate of 1-3°C/10min at a preset temperature in the beating step. During the cooling process, the crystals will grow rapidly and massively. At the end of the cooling, that is, when the gradient cooling reaches the end point, most of the sucralose in the solution has been crystallized out.
  • the second preset time is not limited. In some embodiments, the second preset time is 0.5h ⁇ 3h. If the second preset time is shorter than 0.5h, the crystallization time is too short, the crystallization cannot be carried out completely, and some sucralose remains in the crude sucralose product slurry; if the second preset time is longer than 3h, the crystallization time is too long , resulting in irregular and complex crystal forms of sucralose.
  • the present invention Compared with the existing butyl acetate extraction and purification process of sucralose, the present invention has the following advantages:
  • the operation is simple, the disposal capacity is small, and the amount of solvent required is small;
  • test methods used in the various embodiments and comparative examples in the present application are described below, and will not be repeated in each embodiment.
  • the crude sucralose product that is, the sucralose reaction solution
  • the sucralose reaction solution can be obtained from a commercially available finished product or produced by any method in the prior art, including but not limited to single-gene protection, multiple Group protection method, enzymatic catalysis method, etc. are not limited in this application.
  • ethyl acetate, distilled water, standard substances, etc. are also needed, and the above-mentioned medicines can all be commercially available products, and the distilled water can also be self-made distilled water in the laboratory, which is not used in this application. limit.
  • the recovery rate in each embodiment and the comparative example is the mass percent of the total content of sucralose in the reaction solution of the obtained sucralose solid and sucralose, and wherein the total content of sucralose in the reaction solution of sucralose can be efficiently Liquid chromatography determination.
  • FIG. 4 shows the high-performance liquid chromatogram of the sucralose crude product reaction solution
  • FIG. 5 is the high-performance liquid chromatogram of the sucralose treated by the method of Example 1.
  • the HPLC purity of sucralose in Fig. 4 is about 94% (in terms of the peak area ratio of the high performance liquid chromatogram)
  • the HPLC purity of sucralose in Fig. 5 is greater than 97% (97.36% in terms of the peak area ratio of the high-performance liquid chromatogram)
  • sucralose crystals obtained in Example 4 dissolve in 100 mL of deionized water, heat to 60 ° C, stir to dissolve all the sucralose, add 2 g of activated carbon, maintain at 60 ° C, stir for 1 hour, and then filter while hot to Remove the activated carbon, collect the filtrate, and slowly cool the filtrate to 25°C within 6 hours. At this time, a large number of sucralose crystals are precipitated in the system. Filter and collect the sucralose crystals, which is the refined sucralose, and its HPLC purity More than 99% (calculated in terms of the peak area ratio of the high performance liquid chromatogram), the recovery rate is 70%.
  • the purifying method of the sucralose of the present application has the advantages such as easy and simple operation, little disposal capacity, few required solvent amounts;
  • the solvent widely used in the chlorination step so the use of ethyl acetate will not increase the extra species in the technological process, and the boiling point of ethyl acetate is much lower than that of butyl acetate, so that the energy consumption in the distillation and recovery process is greatly reduced. It is beneficial to improve production efficiency and reduce production costs.

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Abstract

一种三氯蔗糖的提纯方法，包括：从三氯蔗糖反应液中去除溶剂，得到三氯蔗糖粗产品浓缩溶液；在搅拌的条件下，向所述三氯蔗糖粗产品浓缩溶液中加入乙酸乙酯，加热至预设温度，并保持第一预设时间，得到含有部分三氯蔗糖结晶的粗产品浆液；将所述粗产品浆液经梯度降温至温度终点，并保持第二预设时间，经过滤得到三氯蔗糖晶体。具有操作简便，处置容量小、所需溶剂量少等优点；另外，使用乙酸乙酯不会增加工艺流程中额外的物种，且乙酸乙酯的沸点远低于乙酸丁酯，使得在蒸馏脱除回收过程中的耗能大大减少，有利于提高生产效率，降低生产成本。

Description

三氯蔗糖的提纯方法 技术领域
本申请属于精细化工制造领域，具体涉及一种三氯蔗糖的提纯方法。
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(如附图1所示)，即：蔗糖活性最高的6位羟基被选择性保护，通常是以乙酸酯的形式，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-乙酯再脱去乙酰基保护，最终合成了三氯蔗糖。
对于三氯蔗糖工艺的改进，目前主要集中在多步的合成工艺上，而对于三氯蔗糖的提纯工艺的改进则比较少。现有技术中对三氯蔗糖的提纯主要是采用大量的乙酸丁酯为萃取溶剂对三氯蔗糖粗产品水溶液进行萃取，存在着溶剂用量大，产生了大量的有机废液的缺陷；另外，由于乙酸丁酯沸点高导致后续的脱除工艺耗能较高，且乙酸丁酯的使用增加了工艺体系中需操作的物料种类。这些都增加了生产成本，且不利于清洁生产，故而对三氯蔗糖提纯工艺的改进还有很大的空间。
发明内容
鉴于上述问题，针对现有技术中采用的乙酸丁酯萃杂提纯三氯蔗糖工艺，存在操作繁琐、溶剂耗用量大、溶剂脱除耗能高且额外增加处置成本等问题，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三氯蔗糖的提纯方法。
根据本申请的一方面，提供了一种三氯蔗糖的提纯方法，包括：
浓缩步骤：从三氯蔗糖反应液中去除溶剂，得到三氯蔗糖粗产品浓缩溶液；
打浆步骤：在搅拌的条件下，向所述三氯蔗糖粗产品浓缩溶液中加入乙酸乙酯，加热至预设温度，并保持第一预设时间，得到含有部分三氯蔗糖结晶的粗产品浆液；
收集步骤：在搅拌的条件下，将所述粗产品浆液经梯度降温至温度终点，并保持第二预设时间，得到三氯蔗糖晶体。
根据本申请的另一方面，提供了一种三氯蔗糖，其是采用上述的方法制得的，且制得的三氯蔗糖的HPLC纯度≥97％。
本申请的有益效果在于：相较于现有应用广泛的乙酸丁酯萃杂工艺，提出了一种直接对三氯蔗糖粗产品的浓缩物进行打浆处理，不需要将三氯蔗糖粗产品再溶解成溶液的提纯方法，本申请的三氯蔗糖的提纯方法具有操作简便、处置容量小、所需溶剂量少等优点；另外，因为乙酸乙酯是生成三氯蔗糖工艺流程(如氯化步骤)中广泛使用的溶剂，故使用乙酸乙酯不会增加工艺流程中额外的物种，且乙酸乙酯的沸点远低于乙酸丁酯，使得在蒸馏脱除回收过程中的耗能大大减少，有利于提高生产效率，降低生产成本。
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示出了现有技术中三氯蔗糖单基因保护法的工艺流程示意图；
图2示出了现有技术中一种采用乙酸丁酯萃取三氯蔗糖的工艺流程示意图；
图3示出了根据本申请的一个实施例的三氯蔗糖的提纯方法的工艺流程示意图；
图4示出了三氯蔗糖粗产品反应液的高效液相色谱图；
图5是经实施例1的方法处理后的三氯蔗糖的高效液相色谱图。
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。
本申请的发明构思在于：由于三氯蔗糖的极性较大，在水中的溶解度远大于在乙酸乙酯中的溶解度，而在脱乙酰基反应得到的三氯蔗糖粗产品中，存在的杂质多为极性小的物种，通过研究，本申请发现，使用乙酸乙酯对三氯蔗糖粗产品进行打浆处理，可选择性地除去多种杂质，取得很好的提纯效果。
图2示出了现有技术中一种采用乙酸丁酯萃取三氯蔗糖的工艺流程示意图，如图2所示，首先将含有三氯蔗糖粗产品的脱乙酰基反应液浓缩以除去溶剂，然后再加入水溶解，形成三氯蔗糖粗产品的水溶液，再以乙酸丁酯对水溶液进行萃取，以除去杂质，再对除杂后的水溶液进行精制，精制可以为结晶等方法，精制后得到纯化了的三氯蔗糖。由于需要使用高沸点的乙酸丁酯，因此存在着溶剂用量大、耗能高、增加消耗的原料物种等缺陷。
图3示出了根据本申请的一个实施例的三氯蔗糖的提纯方法的工艺流程示意图，该三氯蔗糖的提纯方法包括：
浓缩步骤：从三氯蔗糖反应液中去除溶剂，得到三氯蔗糖粗产品浓缩溶液。
本申请提供的三氯蔗糖的提纯方法是针对在三氯蔗糖的制备过程中，在三氯蔗糖-6乙酸酯发生脱乙酰基反应后生成的含有三氯蔗糖粗产品的混合溶液进行的，其目的是采用一定的技术手段，从含有三氯蔗糖粗产品的混合溶液中提纯三氯蔗糖，在本申请中，将含有三氯蔗糖粗产品的混合溶液称为三氯蔗糖反应液。
本申请提供的三氯蔗糖的提纯方法，首先将三氯蔗糖反应液中的大量有机溶剂进行去除，去除方法了采用本领域中的常规手段，在本申请中的一些实施例中，采用减压蒸馏或常压蒸馏的方法，对有机溶剂进行去除后，得到了含有三氯蔗糖粗产品的浓缩溶液，称为三氯蔗糖粗产品浓缩溶液。
打浆步骤：在搅拌的条件下，向三氯蔗糖粗产品浓缩溶液中加入乙酸乙酯，加热至预设温度，并保持一段时间，记为第一预设时间，得到含有部分三氯蔗糖结晶的粗产品浆液。
如图2所示，在现有技术中，在对三氯蔗糖反应液去除溶剂后，通常采用大量的水对将去除溶剂后的三氯蔗糖反应液进行溶解，得到含三氯蔗糖粗产品的水溶液，然后加入乙酸丁酯进行萃取，利用反应液中各物质的极性不同，将杂质萃取至乙酸丁酯中，萃取完成后，对得到的水溶液进行浓缩结晶，即可得到三氯蔗糖晶体。
而在本申请中，不采用大量的水对去除溶剂后的三氯蔗糖反应液进行溶解，而是直接向三氯蔗糖粗产品浓缩溶液中，加入乙酸乙酯，并在预设条件下，将三氯蔗 糖粗产品浓缩溶液打浆。在这个过程中，三氯蔗糖反应液中多种极性小的有机杂质会进入到乙酸乙酯中，然后经过后续步骤，过滤除去含有杂质的乙酸乙酯母液，从而达到去除三氯蔗糖反应液中的杂质的目的。
在打浆的过程中，大部分三氯蔗糖晶体会从浆液中析出。在本申请中的打浆步骤中，由于不需要使用大量的水对去除溶剂后的三氯蔗糖反应液进行溶解，在简化工艺流程的同时，减少了废水的产生量，并节约了很大的耗能。
收集步骤：在搅拌的条件下，将三氯蔗糖粗产品浆液经梯度降温至温度终点，并保持第二预设时间，得到三氯蔗糖晶体。
该收集步骤的目的是通过降温促进三氯蔗糖晶体的完全析出。在打浆完成后，不需要再将乙酸乙酯从三氯蔗糖反应液中分离出来，而是直接将含有部分三氯蔗糖结晶的粗产品浆液进行梯度降温，以使未析出的三氯蔗糖从反应液中结晶析出。具体的，在搅拌的条件下，将三氯蔗糖粗产品浆液经梯度降温至温度终点，并保持一段时间，记为第二预设时间，经过滤后即可得到三氯蔗糖晶体。
在本申请的一些实施例中，上述的三氯蔗糖的提纯方法还可以包括精制步骤：对得到的三氯蔗糖进行进一步精制，得到精制三氯蔗糖晶体。
为了得到更高纯度的三氯蔗糖晶体，可以将得到的三氯蔗糖进行进一步精制，在本申请中的一些实施例中，对得到的三氯蔗糖进行重结晶处理，得到纯度进一步提高的三氯蔗糖。
本实施例推荐一种三氯蔗糖的重结晶方法，包括：溶解步骤：将三氯蔗糖放入去离子水中加热溶解，并以活性炭脱色，过滤，得到重结晶溶液；浓缩步骤：将重结晶溶液蒸发浓缩至预设浓度；晶核生成步骤：将浓缩后的重结晶溶液在预设温度下静置一段时间，以形成三氯蔗糖晶核；结晶生成步骤：将含有晶核的重结晶溶液进行梯度降温，获得含有大量三氯蔗糖晶体的重结晶溶液；过滤步骤：将所述含有大量三氯蔗糖结晶的重结晶溶液离心、水洗、干燥，获得三氯蔗糖晶体。
乙酸乙酯的用量
在本申请中，对乙酸乙酯的用量不做限制，在一些实施例中，以每克三氯蔗糖粗产品浓缩溶液为基准，所述乙酸乙酯的体积用量为0.2～0.5mL。若乙酸乙酯的体积用量少于0.2mL/1克三氯蔗糖粗产品溶液，则用量过少，不能够完全将三氯蔗糖反应液中的有机杂质萃取出来；若乙酸乙酯的体积用量多于0.5mL/1克三氯蔗糖粗产品溶液，则用量过多，一方面造成了乙酸乙酯不必要的浪费，另一方面导致 三氯蔗糖粗产品浆液浓度过低，不利于三氯蔗糖后续结晶，甚至造成生成的三氯蔗糖结晶不完全、晶型复杂多样、收率偏低等问题。
打浆步骤中的预设温度
在本申请中，对打浆步骤中的预设温度不做限制，在一些实施例中，预设温度为45℃～65℃。如果预设温度低于45℃，则打浆温度过低，乙酸乙酯不能很好地与三氯蔗糖粗产品浓缩溶液混合均匀；如果预设温度高于65℃，则打浆温度过高，容易造成三氯蔗糖粗产品浓缩溶液局部过热，甚至爆沸，以及乙酸乙酯的无效挥发。
打浆步骤中的第一预设时间
在本申请中，第打浆步骤中的第一预设时间，即打浆时间不做限制，在一些实施例中，第一预设时间为0.5h～3h。若第一预设时间短于0.5h，则打浆时间过短，即萃取时间过短，多种有机杂质不能完全进入乙酸乙酯中；若第一预设时间高于3h，则打浆时间过长，即萃取时间过长，造成整体提纯工艺时间过长，且不能带来其他有益效果。
梯度降温工艺
在本申请中，收集步骤中的梯度降温工艺的目的是促进未析出的三氯蔗糖晶体的快速、大量析出。本申请对收集步骤中的梯度降温工艺不做限制，在一些实施例中，梯度降温为以1～3℃/10min的速度降温至温度终点；温度终点为0～10℃。
在三氯蔗糖粗产品浆液的基础上采用梯度降温，可以使三氯蔗糖晶体大量的析出。在一些实施例中，梯度降温是在打浆步骤中的预设温度上在以1～3℃/10min的速度降温至0～10℃。在降温的过程中，晶体会快速大量的生长，在降温结束时，即梯度降温达到终点时，溶液中的三氯蔗糖已大部分结晶析出。
在结晶步骤中，在将三氯蔗糖粗产品浆液通过梯度降温降至温度终点后，保持一段时间，记为第二预设时间，在本申请中，对第二预设时间不做限制，在一些实施例中，第二预设时间为0.5h～3h。若第二预设时间短于0.5h，结晶时间过短，结晶不能进行彻底，还有部分三氯蔗糖留在三氯蔗糖粗产品浆液中；若第二预设时间长于3h，结晶时间过长，导致三氯蔗糖晶型不规则，晶型复杂。
相比于现有的乙酸丁酯萃杂提纯三氯蔗糖工艺，本发明具有如下优点：
第一，操作简便，处置容量小，所需的溶剂量少；第二，使用乙酸乙酯，可以直接回收套用于三氯蔗糖的生产体系中，不会增加整个工艺流程中需处理的物料种类；第三，乙酸乙酯的沸点较低，使得在蒸馏脱除回收过程中的耗能大大减少；第 四，制得三氯蔗糖，具有纯度高、便于进一步纯化精制的特点，其HPLC纯度可达97％或以上。
本申请中涉及的药品来源或测试方法：
本申请中各实施例和对比例中采用的测试手段如下所述，在各个实施例中不再赘述。
三氯蔗糖反应液的来源
在本申请的一些实施例中，三氯蔗糖粗产品，即三氯蔗糖反应液可来自市售成品或通过现有技术中的任意一种方法进行生产，包括但不限于单基因保护法、多基团保护法、酶催化法等，在本申请中不做限制。
其他药品
在本申请的一些实施例中，还需要用到乙酸乙酯、蒸馏水、以及标准物质等，上述药品均可采用市售产品，其中，蒸馏水也可采用实验室自制蒸馏水，在本申请中不做限制。
三氯蔗糖纯度的分析和测定条件：
本申请中涉及的三氯蔗糖纯度分析测试方法可参考《食品添加剂国家标准GB 25531-2010食品添加剂三氯蔗糖》。
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、三氯蔗糖标准(纯度99.9％)，外标法测量含量。
回收率的计算方法：
各实施例和对比例中的回收率为得到的三氯蔗糖固体与三氯蔗糖的反应液中三氯蔗糖总含量的质量百分比，其中三氯蔗糖的反应液中三氯蔗糖总含量可采用高效液相色谱测定。
实施例1
在一容积为250mL的带有机械搅拌装置的三口圆底烧瓶中，装入80g脱去溶剂的含有三氯蔗糖的反应液浓缩溶液，向其中加入20mL乙酸乙酯。开启搅拌，在 搅拌的条件下，升温至55℃，保温搅拌2小时，打浆完成，这时三口烧瓶内已有大量三氯蔗糖固体析出。然后每10分钟降温2℃，将体系降至5℃，并维持在5℃，搅拌1小时，再对体系进行过滤，收集固体，得到纯化后的三氯蔗糖，HPLC纯度为97％(以高效液相色谱图峰面积占比计)，回收率为85％。
图4示出了三氯蔗糖粗产品反应液的高效液相色谱图，图5是经实施例1的方法处理后的三氯蔗糖的高效液相色谱图。请同时参考图4和图5，其中，图4中的三氯蔗糖HPLC纯度约为94％(以高效液相色谱图峰面积占比计)，图5中的三氯蔗糖HPLC纯度大于97％(以高效液相色谱图峰面积占比计为97.36％)，由此可见，本申请的方法对三氯蔗糖的提纯效果显著。
实施例2
在一容积为250mL的带有机械搅拌装置的三口圆底烧瓶中，装入80g脱去溶剂的含有三氯蔗糖的反应液浓缩物，向其中加入40mL乙酸乙酯。开启搅拌，在搅拌的条件下，升温至60℃，保温搅拌1小时，这时体系有大量三氯蔗糖固体析出。然后每10分钟降温3℃，将体系将至0℃，维持在0℃，搅拌2小时，再对体系进行过滤，收集固体，得到纯化后的三氯蔗糖，HPLC纯度大于98％(以高效液相色谱图峰面积占比计)，回收率为78％。
实施例3
在一容积为250mL的带有机械搅拌装置的三口圆底烧瓶中，装入80g脱去溶剂的含有三氯蔗糖的反应液浓缩物，向其中加入30mL乙酸乙酯。开启搅拌，在搅拌的条件下，升温至50℃，保温搅拌3小时，这时体系有大量三氯蔗糖固体析出。然后每10分钟降温1℃，将体系将至8℃，维持在8℃，搅拌3小时，再对体系进行离心，收集固体，得到纯化后的三氯蔗糖，HPLC纯度大于97％(以高效液相色谱图峰面积占比计)，回收率为82％。
实施例4
在一容积为500mL的带有机械搅拌装置的三口圆底烧瓶中，装入200g脱去溶剂的含有三氯蔗糖的反应液浓缩物，向其中加入50mL乙酸乙酯。开启搅拌，在搅拌的条件下，升温至60℃，保温搅拌3小时，这时体系有大量三氯蔗糖固体析出。 然后每10分钟降温1℃，将体系将至5℃，维持在5℃，搅拌3小时，再对体系进行离心，收集固体，得到纯化后的三氯蔗糖，HPLC纯度大于98％(以高效液相色谱图峰面积占比计)，回收率为85％。
实施例5(三氯蔗糖晶体的进一步精制)
取100g实施例4中得到的三氯蔗糖晶体，溶于100mL去离子水中，加热至60℃，搅拌使三氯蔗糖全部溶解，加入2g活性炭，维持60℃，搅拌1小时，再趁热过滤以除去活性炭，收集滤液，并使滤液在6小时内缓慢降温至25℃，此时体系中有大量三氯蔗糖晶体析出，过滤，收集三氯蔗糖晶体，即为精制的三氯蔗糖，其HPLC纯度大于99％(以高效液相色谱图峰面积占比计)，回收率为70％。
对比例1
在一容积为500mL的带有机械搅拌装置的三口圆底烧瓶中，装入80g脱去溶剂的含有三氯蔗糖的反应液浓缩物，向其中加入250mL水，溶解，形成水溶液。再加入200毫升乙酸丁酯，开启搅拌，在室温下搅拌1小时，以使乙酸丁酯充分萃取水溶液中的杂质。然后静置，分出水相，其中的三氯蔗糖HPLC纯度约为95％(以高效液相色谱图峰面积占比计)，回收率为90％。
通过上述实施例与对比例可以看出，相较于现有应用广泛的乙酸丁酯萃杂工艺，提出了一种直接对三氯蔗糖粗产品的浓缩物进行打浆处理，不需要将三氯蔗糖粗产品再溶解成溶液的提纯方法，本申请的三氯蔗糖的提纯方法具有操作简便、处置容量小、所需溶剂量少等优点；另外，因为乙酸乙酯是生成三氯蔗糖工艺流程(如氯化步骤)中广泛使用的溶剂，故使用乙酸乙酯不会增加工艺流程中额外的物种，且乙酸乙酯的沸点远低于乙酸丁酯，使得在蒸馏脱除回收过程中的耗能大大减少，有利于提高生产效率，降低生产成本。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制；任何熟悉本领域的技术人员，在不脱离本发明技术方案范围情况下，都可利用上述揭示的方法和技术内容对本发明技术方案做出许多可能的变动和修饰，或修改为等同变化的等效实施例。因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同替换、等效变化及修饰，均仍属于本发明技术方案保护的范围内。

Claims (10)

  1. 一种三氯蔗糖的提纯方法，其特征在于，包括：
    浓缩步骤：从三氯蔗糖反应液中去除溶剂，得到三氯蔗糖粗产品浓缩溶液；
    打浆步骤：在搅拌的条件下，向所述三氯蔗糖粗产品浓缩溶液中加入乙酸乙酯，加热至预设温度，并保持第一预设时间，得到含有部分三氯蔗糖结晶的粗产品浆液；
    收集步骤：在搅拌的条件下，将所述粗产品浆液经梯度降温至温度终点，并保持第二预设时间，经过滤得到三氯蔗糖晶体。
  2. 根据权利要求1所述的方法，其特征在于，还包括:
    精制步骤：对得到的所述三氯蔗糖晶体进行精制，以进一步提高三氯蔗糖晶体纯度。
  3. 根据权利要求2所述的方法，其特征在于，所述精制为重结晶。
  4. 根据权利要求1或2所述的方法，其特征在于，以每克三氯蔗糖粗产品浓缩溶液为基准，所述乙酸乙酯的体积用量为0.2～0.5mL。
  5. 根据权利要求1或2所述的方法，其特征在于，在打浆步骤中，所述预设温度为45℃～65℃。
  6. 根据权利要求1或2所述的方法，其特征在于，在打浆步骤中，所述第一预设时间为0.5h～3h。
  7. 根据权利要求1或2所述的方法，其特征在于，在结晶步骤中，所述梯度降温为以1～3℃/10min的速度降温至温度终点；所述温度终点为0～10℃。
  8. 根据权利要求1或2所述的方法，其特征在于，在结晶步骤中，所述第二预设时间为0.5h～3h。
  9. 根据权利要求1或2所述的方法，其特征在于，在浓缩步骤中，所述去除溶剂采用减压蒸馏或常压蒸馏。
  10. 一种三氯蔗糖，其特征在于，采用上述权利要求1-9中任意一项所述的方法制得，所述三氯蔗糖的HPLC纯度≥97％。
PCT/CN2020/128654 2020-11-13 2020-11-13 三氯蔗糖的提纯方法 WO2022099606A1 (zh)

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