WO2022141227A1

WO2022141227A1 - Preparation method for sucralose, crude product solution, and sucralose

Info

Publication number: WO2022141227A1
Application number: PCT/CN2020/141525
Authority: WO
Inventors: 赵金刚; 夏家信; 许传久; 周万全
Original assignee: 安徽金禾实业股份有限公司
Priority date: 2020-12-30
Filing date: 2020-12-30
Publication date: 2022-07-07
Also published as: CN112771060A

Abstract

The present application provides a preparation method for sucralose and a crude product solution thereof. The preparation method comprises: dissolving sucralose-6-ethyl ester in methanol to form a sucralose-6-ethyl ester reaction solution; adding tert-butylamine to the sucralose-6-ethyl ester reaction solution as a catalyst for reaction under a preset condition, so that the sucralose-6-ethyl ester undergoes a deacylation reaction to form a sucralose mixed solution; and distilling the sucralose mixed solution to obtain a sucralose crude product solution. The present application has the following beneficial effects: by using volatile tert-butylamine as a catalyst, the catalyst can be removed and recycled only by means of a simple distillation process while efficiently and reliably catalyzing the deacylation reaction of the sucralose-6-ethyl ester, thereby simplifying the process step of catalyst separation, reducing material consumption and wastewater generation, and greatly reducing the production cost of sucralose; and clean production is facilitated.

Description

Preparation method of sucralose, crude product solution and sucralose

technical field

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.

Background of the Invention

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. So far, 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 acetate, that is, to generate sucrose-6-ethyl ester, sucrose-6-ethyl ester The three hydroxyl groups at the 4, 1' and 6' positions of sucralose are selectively chlorinated to generate sucralose-6-ethyl ester, and the sucralose-6-ethyl ester is deacetylated to generate sucralose.

For the deacetylation step, 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. . The use of MeONa/MeOH catalytic system has the advantages of mild conditions, rapid reaction and high yield, but it also has certain disadvantages, such as cumbersome process steps, large solvent consumption, and large amount of waste water from resin regeneration; MeONa is relatively expensive and cannot be recycled. , increased production costs, etc.

Therefore, there is still a lot of room for improvement and improvement in the process of synthesizing sucralose by removing acyl groups from sucralose-6-ethyl ester. It should be noted that the statements herein merely provide background information related to the present application and do not necessarily constitute prior art.

SUMMARY OF THE INVENTION

In view of the above problems, 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.

According to one aspect of the present application, a preparation method of sucralose is provided, comprising:

Dissolving step: dissolving sucralose-6-ethyl ester in methanol to form a sucralose-6-ethyl ester reaction solution;

Catalysis step: adding tert-butylamine as a catalyst 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; and

Impurity removal step: the mixed solution of sucralose is distilled to obtain a crude product solution of sucralose.

According to another aspect of the present application, a sucralose crude product solution is provided, which is prepared by the above-mentioned preparation method.

According to another aspect of the present application, a sucralose is provided, which is obtained by crystallizing and refining the sucralose crude product solution obtained above.

To sum up, the beneficial effects of the present application are: using volatile organic amines as catalysts, while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester, it can be separated by a simple distillation process The catalyst is recovered and utilized, which simplifies the process steps of separating the catalyst, reduces material consumption and waste water generation, greatly reduces the production cost of sucralose, and is beneficial to clean production.

The above description is only an overview of the technical solution of the present application, in order to be able to understand the technical means of the present application more clearly, it can be implemented according to the content of the description, and in order to make the above-mentioned and other purposes, features and advantages of the present application more obvious and easy to understand , and the specific embodiments of the present application are listed below.

Brief Description of Drawings

Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are for purposes of illustrating preferred embodiments only and are not to be considered limiting of the application. Also, the same components are denoted by the same reference numerals throughout the drawings. In the attached image:

FIG. 1 shows a schematic flowchart of a method for preparing sucralose according to an embodiment of the present application.

MODES OF IMPLEMENTING THE INVENTION

Exemplary embodiments of the present application will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present application are shown in the drawings, it should be understood that the present application may be embodied in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that the application will be more thoroughly understood, and will fully convey the scope of the application to those skilled in the art.

Although MeONa/MeOH (MeONa/MeOH represents the coexistence of the two, specifically using MeONa as a catalyst and MeOH as a solvent) system is a classic combination, it is widely used in the deacetylation of sugars (ie Zemplén reaction), but the MeONa/MeOH system is widely used. As a catalyst, there are many disadvantages. For example, the sodium ions brought in by the catalyst MeONa often need to be removed by a cationic resin. The process is complicated and tedious, and the catalyst cannot be recycled; and in the process, the regeneration of the resin will also produce a large amount of waste water, which is not conducive to cleaner production.

The idea of the present application is to use a highly volatile organic amine as a catalyst, while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester, the catalyst can be separated and recycled through a simple distillation process, which not only simplifies The process steps of separating the catalyst are reduced, the consumption of materials and the generation of waste water are reduced, the production cost of sucralose is reduced to a great extent, and it is beneficial to clean production.

Fig. 1 shows the schematic flow sheet of the preparation method of sucralose according to an embodiment of the present application, including:

In the dissolving step S110, sucralose-6-ethyl ester is dissolved in methanol to form a sucralose-6-ethyl ester reaction solution.

First, 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 tert-butylamine as a catalyst 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.

At present, the most widely used method for preparing sucralose is the single-group protection method. Taking sucralose-6-acetate as an example, the reaction process is shown in reaction formula (1).

Reaction (1)

From the reaction formula (1), it can be seen that the 6-position hydroxyl group has the highest activity of sucrose. In the single-group protection method, a carboxylic acid such as acetic acid is used to protect it. Specifically, taking acetic acid as an example, the sucrose is It is esterified with acetic acid 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. For the protection of the hydroxyl group, the substitution of the hydroxyl group at the 6-position by a chlorine atom is avoided.

The present application mainly improves the step of deacylation. In the prior art, sodium methoxide is usually used as a catalyst and methanol is used as a solvent to carry out the deacetylation reaction. After the deacylation reaction is completed, the obtained reaction mixture is usually treated with a cationic resin to remove sodium ions, and the treatment process is shown in reaction formula (2).

Reaction (2)

As can be seen from the reaction formula (2), after the deacylation reaction is completed, a cationic resin is added to the obtained reactant mixture, which can exchange cations with the generated sodium alkoxide, and the sucralose crude product solution is separated by filtration, The resin after cation exchange can be regenerated, and the cation resin can be reused again. In this process, the catalyst sodium methoxide cannot be reused, resulting in a lot of waste, and the regeneration process of the resin will consume a lot of acid and alkali and generate a lot of waste water.

In view of the above situation, in the Zemplén reaction system, the inventors found that MeONa can be replaced by many different types of bases, which can be strong bases, weak bases, organic bases or inorganic bases, etc., as well as immobilized bases such as basic anion resins All forms of bases can catalyze the deacetylation process very smoothly. The application uses volatile tert-butylamine as a catalyst. On the one hand, it can catalyze the deacylation reaction of sucralose-6-ethyl ester efficiently and reliably; on the other hand, tert-butylamine can be separated, recovered and reused by simple distillation, reducing The consumption of materials such as catalysts and cation resins is reduced, and the amount of waste water produced is reduced.

After a catalytic step, 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.

And the impurity removal step S130: Distilling the sucralose mixed solution to obtain a crude sucralose product solution.

Tert-butylamine is a volatile organic matter, therefore, after the reaction is completed, the tri-filtered sucrose mixed solution obtained above is distilled to remove the catalyst. In the present application, the method for removing the catalyst is very simple, and only needs simple conventional means. The process of using cation resin to remove sodium ions is omitted, thereby reducing material loss and waste water generation, which is beneficial to clean production and greatly saves process costs.

As shown in Figure 1, using volatile tert-butylamine as a catalyst, while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester, the catalyst can be separated and recycled through a simple distillation process, which simplifies the The process step of separating the catalyst reduces material consumption and waste water generation, greatly reduces the production cost of sucralose, and is beneficial to clean production.

In some embodiments of the present application, the above-mentioned preparation method of sucralose further comprises: a catalyst recovery step: recovering and reusing the catalyst distilled in the impurity removal step.

The tert-butylamine can be separated from the obtained reaction mixture by distillation, and then condensed and recovered, and the recovered tert-butylamine can still catalyze the deacylation reaction again.

In some embodiments of the present application, 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.

In order to further improve the purity of sucralose, sucralose can be purified by adopting one or a combination of existing technologies.

source of medicine

In this application, unless otherwise specified, commercially available products can be used for conventional medicines, which will not be described in detail.

The amount and source of methanol

In some embodiments of the present application, the amount of methanol is not limited. In other embodiments, the amount of methanol is 3-10 mL by volume based on each gram of sucralose-6-ethyl ester. ; 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. , and can not bring other beneficial effects, and will increase the disposal amount of solvent removal in the subsequent sucralose crystallization process.

The type and amount of catalyst

In some embodiments of the present application, volatile tert-butylamine is selected as the catalyst. Tert-butylamine can catalyze the deacylation reaction of sucralose-6-ethyl ester well, and has volatility, which can be removed by distillation and is easy to recover. use.

In some embodiments of the present application, the amount of tert-butylamine is 0.02-0.2 grams by mass based on each gram of sucralose-6-ethyl ester.

Taking every gram of sucralose-6-ethyl ester as a benchmark, if the consumption of tert-butylamine is less than 0.02g by mass, the catalyst consumption is too small, and it is impossible to catalyze the complete deacylation of sucralose-6-ethyl ester in a short time. ; Taking every gram of sucralose-6-ethyl ester as a benchmark, if the consumption of tert-butylamine is greater than 0.2g by mass, the catalyst consumption is too much, there is no obvious benefit, causing waste of materials, and causing the reaction solution to be too alkaline. Strong, may also cause unwanted side effects.

preset conditions

In some embodiments of the present application, in the catalytic step, 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. If the 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, it may cause unnecessary side effects.

Distillation conditions

In some embodiments of the present application, in the impurity removal step, the distillation conditions are not limited. In other embodiments, the distillation temperature of the distillation is 20-60° C., the distillation pressure is 10-100 kPa, and the distillation time is 0.5～6h. If the distillation temperature is less than 20°C, the distillation pressure is greater than 100kPa, and the distillation time is less than 0.5h, the degree of distillation is insufficient and the catalyst cannot be completely removed; if the distillation temperature is greater than 60°C, the distillation pressure is less than 10kPa, and the distillation time is greater than 6h, the distillation is excessive. , resulting in a waste of time and energy consumption, and can not bring other beneficial effects.

Types and sources of sucralose-6-ethyl ester

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, which is not limited in this application.

Reaction formula (3) shows the reaction process of the preparation method of sucralose according to another embodiment of the present application. It can be seen from reaction formula (3) that methanol is used as a solvent and tert-butylamine is used as a catalyst to remove the sucralose. Acyl reaction is used to prepare sucralose. In addition to sucralose, the products also include ethyl formate and tert-butylamine. The tert-butylamine is evaporated and removed, and it can be recycled, thereby saving process and material consumption.

Reaction (3)

Measurement method

The test instruments and test conditions of the high performance liquid chromatography involved in this application are as follows:

Shimadzu high performance liquid chromatograph, equipped with RID-10A differential refractive index detection, LC-10ADVP high pressure pump, CTO-10ASVP incubator; chromatographic column: Agilent XDB C18 column (250mm×4.6mm, 5μm); mobile phase: methanol- 0.125% dipotassium hydrogen phosphate aqueous solution (4:6); column temperature: 30°C; flow rate: 1.0 mL/min. Among them, methanol (chromatographic grade), dipotassium hydrogen phosphate (analytical grade), ultrapure water, and other standard substances are required, and the content is measured by the external standard method.

In this application, high performance liquid chromatography can be used to determine the content of sucralose-6-ethyl ester and sucralose, which will not be repeated in each embodiment.

Yield calculation method:

In each embodiment and comparative example, 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.

Compared with the prior art, the process is simple and easy to operate, saves materials, and obtains a crude product solution of sucralose obtained by any of the above-mentioned methods, and obtains high-purity sucralose by crystallization and refining of the obtained crude product solution of sucralose. Sucralose crystals. Crystallization can be achieved by one or a combination of methods in the prior art.

Example 1

In a three-necked round-bottomed flask with a volume of 1000 ml, add 100 grams of fully dried sucralose-6-ethyl ester, add 300 ml of methanol, and fully dissolve to form a homogeneous solution. A mechanical stirring device was equipped on the flask, the stirring was turned on, and 3 g of tert-butylamine was added dropwise using a dropping funnel. After the addition was completed, and the reaction was maintained at 50° C. for 12 hours, high performance liquid chromatography showed that the remaining sucralose-6-ethyl ester was ≤ 0.5% (relative peak area), and the stirring was stopped. Using a rotary evaporator at a temperature of 30°C and a pressure of 80kPa, the reaction solution was distilled, and the distilled fraction was about 150 ml, which was a mixture of tert-butylamine and methanol. At this time, the tert-butylamine in the reaction solution had been removed. The sucralose product is further purified by conventional methods. The yield of sucralose from the deacetylation of sucralose-6-ethyl ester was determined to be 88% by high performance liquid chromatography.

Example 2

In a three-necked round-bottomed flask with a volume of 2000 ml, add 100 grams of fully dried sucralose-6-ethyl ester, add 1000 ml of methanol, and fully dissolve to form a homogeneous solution. Equipped with a mechanical stirring device on the flask, turned on stirring, and added 20 grams of tert-butylamine dropwise using a dropping funnel. After the addition was completed, the reaction was maintained at room temperature (25° C.) for 2 hours, and high performance liquid chromatography showed that the remaining sucralose-6-ethyl ester was less than or equal to 0.5% (relative peak area), and the stirring was stopped. Using a rotary evaporator at a temperature of 50°C and a pressure of 20kPa, the reaction solution was distilled, and the distilled fraction was about 400 ml, which was a mixture of tert-butylamine and methanol. At this time, the tert-butylamine in the reaction solution had been removed. The sucralose product is further purified by conventional methods. The yield of sucralose from the deacetylation reaction of sucralose-6-ethyl ester determined by high performance liquid chromatography was 85%.

Example 3

In a three-necked round-bottomed flask with a volume of 1000 ml, add 100 grams of fully dried sucralose-6-ethyl ester, add 600 ml of methanol, and fully dissolve to form a homogeneous solution. Equipped with a mechanical stirring device on the flask, turned on stirring, and added 2 g of tert-butylamine dropwise using a dropping funnel. After the addition was completed, the reaction was maintained at 40° C. for 24 hours, and high performance liquid chromatography showed that the remaining sucralose-6-ethyl ester was less than or equal to 0.5% (relative peak area), and the stirring was stopped. Using a rotary evaporator at a temperature of 40 ° C and a pressure of 40 kPa, the reaction solution was distilled, and the distilled fraction was about 200 ml, which was a mixture of tertiary butylamine and methanol. At this time, the tertiary butylamine in the reaction solution had been removed. The sucralose product is further purified by conventional methods. The yield of sucralose produced by deacetylation of sucralose-6-ethyl ester was determined by high performance liquid chromatography, and the yield was 82%.

Example 4

In a three-necked round-bottomed flask with a volume of 1000 ml, add 100 grams of fully dried sucralose-6-ethyl ester, add 400 ml of methanol, and fully dissolve to form a homogeneous solution. Equipped with a mechanical stirring device on the flask, turned on stirring, and added 5 g of tert-butylamine dropwise using a dropping funnel. After the addition was completed, the reaction was maintained at room temperature (25° C.) for 6 hours, and high performance liquid chromatography showed that the remaining sucralose-6-ethyl ester was less than or equal to 0.5% (relative peak area), and the stirring was stopped. Using a rotary evaporator at a temperature of 50°C and a pressure of 50kPa, the reaction solution was distilled, and the distilled fraction was about 200 ml, which was a mixture of tert-butylamine and methanol. At this time, the tert-butylamine in the reaction solution had been removed. The sucralose product is further purified by conventional methods. The yield of sucralose from the deacetylation of sucralose-6-ethyl ester was determined to be 92% by high performance liquid chromatography.

Embodiment 5 (recovery tert-butylamine is applied mechanically)

In a three-necked round-bottomed flask with a volume of 1000 ml, add 100 grams of fully dried sucralose-6-ethyl ester, add 300 ml of methanol, and fully dissolve to form a homogeneous solution. The flask was equipped with a mechanical stirring device, the stirring was turned on, and the mixture of 200 ml of tert-butylamine and methanol recovered by distillation in Example 4 was added dropwise using a dropping funnel. After the addition was completed, the reaction was maintained at room temperature (25° C.) for 6 hours, and high performance liquid chromatography showed that the remaining sucralose-6-ethyl ester was less than or equal to 0.5% (relative peak area), and the stirring was stopped. Using a rotary evaporator at a temperature of 50°C and a pressure of 50kPa, the reaction solution was distilled, and the distilled fraction was about 200 ml, which was a mixture of tert-butylamine and methanol. At this time, the tert-butylamine in the reaction solution had been removed. The sucralose product is further purified by conventional methods. The yield of sucralose from the deacetylation of sucralose-6-ethyl ester was determined to be 89% by high performance liquid chromatography.

Comparative Example 1 (Deacetylation of MeONa/MeOH System)

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 add 2 g of sodium methoxide to the solution. Equipped with a mechanical stirring device on the flask, turned on stirring, and maintained the reaction at 25° C. for 6 hours. The residual sucralose-6-ethyl ester was determined by high performance liquid chromatography ≤0.5% (relative peak area), and the stirring was stopped. An appropriate amount of acidic cationic resin was added to the reaction solution, and stirring was maintained at low speed until the pH of the reaction solution was 7. The resin is removed by filtration, and the obtained filtrate contains the crude sucralose product. Further, the sucralose product can be further purified according to conventional methods. In this process, the sodium methoxide used cannot be recycled, and cation resin needs to be used to remove sodium ions, and the acid cation resin used needs to be washed and exchanged with acid and alkali before it can be recycled. A large amount of waste water is produced in the process. The yield of sucralose determined by high performance liquid chromatography was 89%.

It can be seen from Examples 1 to 5 and Comparative Example 1 that using the method of the present application and using tert-butylamine as a catalyst, the catalyst can be separated by distillation while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester , and the mixture of the distilled catalyst and methanol can be reused directly, saving the catalyst post-treatment process.

To sum up, the beneficial effects of the present application are: using volatile tert-butylamine as a catalyst, while efficiently and reliably catalyzing the deacylation reaction of sucralose-6-ethyl ester, the catalyst can be removed by a simple distillation process And recycling, simplifies the process steps of separating the catalyst, reduces material consumption and waste water generation, greatly reduces the production cost of sucralose; and is conducive to clean production.

The above descriptions are only specific implementations of the present application, and those skilled in the art can make other improvements or modifications on the basis of the above-mentioned embodiments under the above teachings of the present application. It should be understood by those skilled in the art that the above-mentioned specific description is only to better explain the purpose of the application, and the protection scope of the application should be based on the protection scope of the claims.

Furthermore, those skilled in the art will appreciate that although some of the embodiments described herein include certain features, but not others, included in other embodiments, that combinations of features of different embodiments are intended to be within the scope of the present application within and form different embodiments. For example, in the following claims, any of the claimed embodiments may be used in any combination.

Claims

A preparation method of sucralose, characterized in that, comprising:

Dissolving step: dissolving sucralose-6-ethyl ester in methanol to form a sucralose-6-ethyl ester reaction solution;

Catalysis step: adding tert-butylamine as a catalyst 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 sucralose mixed solution; and

Impurity removal step: distilling the sucralose mixed solution to obtain a crude sucralose product solution.
The method of claim 1, further comprising:

Catalyst recovery step: the catalyst distilled in the impurity removal step is recovered and reused.
The method of claim 1, further comprising:

In the refining step, the crude sucralose product solution is purified and refined to improve the purity of the sucralose.
The method according to claim 1, characterized in that, based on per gram of sucralose-6-ethyl ester, the consumption of the methanol is 3-10 mL by volume.
The method according to claim 1, characterized in that, based on per gram of sucralose-6-ethyl ester, the consumption of the tert-butylamine is 0.02-0.2 grams by mass.
The method according to claim 1, wherein, in the catalysis step, the preset conditions are: under stirring conditions, the reaction temperature is set to 10-60°C, and the reaction time is set to 0.5-24h.
The method according to claim 1, characterized in that, in the impurity removal step, the distillation temperature of the distillation is 20-60° C., the distillation pressure is 10-100 kPa, and the distillation time is 0.5-6 h.
The method of claim 1, further comprising:

Crystallization step: crystallize and purify the crude sucralose product solution to obtain sucralose crystals.
A sucralose crude product solution, which is prepared by the method described in any one of claims 1 to 7.
A kind of sucralose, which is obtained by adopting the sucralose crude product solution crystallization and refining in claim 9.