A process for the preparation of sucralose-6-ethyl ester

Abstract

The application discloses a preparation method of sucralose-6-ethyl ester. The method comprises the following steps: under the action of a supported catalyst, sucrose-6-ethyl ester and hexachlorocyclohexa-2,5-dienone are subjected to selective chlorination reaction in a solvent to generate sucralose-6-ethyl ester. The method has simple process and mild conditions, avoids the use of phosgene and thionyl chloride, greatly simplifies the post-treatment process, reduces energy consumption, and is easy to separate the used supported catalyst and environment-friendly.

Description

Technical Field

[0001] This invention relates to an organic synthesis method, and more particularly to a method for preparing sucralose-6-ethyl ester. Background Technology

[0002] Sucralose is a fifth-generation artificial sweetener and the only functional sweetener made from sucrose. It has advantages such as low calories, high sweetness, high safety, and pure sweetness. It is currently widely used in a variety of foods such as beverages, condiments, baked goods, and dairy products.

[0003] Existing industrial synthesis routes for sucralose primarily employ a single-group protection method, involving three steps: acylation, chlorination, and alcoholysis. Sucralose-6-ethyl ester, generated via chlorination, is a crucial intermediate in sucralose synthesis, and its yield and purity directly impact the final product's yield and quality. Chlorination has a complex mechanism and produces numerous byproducts. Currently, the main chlorinating agents used in industrial production are phosgene and thionyl chloride. Phosgene's highly toxic nature poses significant safety risks during production, while the thionyl chloride method results in low yields and generates sulfur dioxide waste gas, which negatively impacts product quality and is difficult to treat.

[0004] Patents EP0409549 and CN102439020B mention the use of phosgene as a chlorination reagent. The use of excessive phosgene requires a large amount of alkali to quench the reaction, which not only poses a high safety risk in the process, but also makes the post-processing very complicated and energy-intensive.

[0005] Patents CN101619083B and CN103145772A mention a method for preparing sucralose-6-ethyl ester using thionyl chloride, which has the disadvantages of low yield and high cost, and generates a large amount of waste solvent and sulfur dioxide waste gas, making the three wastes difficult to treat.

[0006] To address the shortcomings of the aforementioned process, there is an urgent need to develop a new method for synthesizing sucralose-6-acetic acid ester, overcoming the problems of low product yield, complex post-processing, and high energy consumption in the existing process. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention proposes a method for preparing sucralose-6-ethyl ester. This method is simple, operates under mild conditions, avoids the use of phosgene and thionyl chloride, significantly simplifies the post-processing steps, and reduces energy consumption. The supported catalyst used is easy to separate and environmentally friendly.

[0008] A method for preparing sucralose-6-ethyl ester includes selectively chlorinating sucralose-6-ethyl ester and hexachlorocyclohexane-2,5-dienone in a solvent under the action of a supported catalyst to generate sucralose-6-ethyl ester.

[0009] sucrose-6-ethyl ester

[0010] Sucralose-6-ethyl ester

[0011] The supported catalyst is referred to as Cu-Cr / X, which includes a Cu main catalyst, a Cr co-catalyst, and an X support. The X support is selected from one or more of activated carbon, carbon nanotubes, molecular sieves, neutral alumina, and silica, preferably one or more of 4A molecular sieves and silica.

[0012] As a preferred embodiment of the present invention, the Cu / Cr content ratio in the supported catalyst is 1:(0.3-0.6), preferably 1:(0.3-0.4), based on the molar ratio of metal elements;

[0013] Preferably, in the supported catalyst, the mass of the support is 8-15 times the mass of Cu, more preferably 10-14 times.

[0014] The supported catalyst can be prepared by at least one of ball milling, co-precipitation, hydrothermal method, adsorption, impregnation and sol-gel method. The present invention does not impose any limitation on this method, but ball milling is preferred from the perspective of operation and use.

[0015] The following are feasible examples of preparing supported catalysts using ball milling:

[0016] S1: Activation of the carrier: Soak the carrier in dilute acid, wash it repeatedly with water and then dry it; the dilute acid can be one or more of hydrochloric acid, sulfuric acid and phosphoric acid with a concentration of 0.01-0.5 mol / L; the soaking temperature is, for example, 20-30℃.

[0017] S2: The Cu-containing compound and the Cr-containing compound are ball-milled and mixed with the activated support to obtain a catalyst precursor; wherein the Cu-containing compound may be selected from one or more of copper chloride, copper sulfate, copper acetate, and copper carbonate, and the Cr-containing compound may be selected from one or more of chromium chloride, chromium sulfate, chromium nitrate, and chromium phosphate; the ball milling is, for example, a planetary ball mill.

[0018] S3: The catalyst precursor is calcined, crushed, and shaped to obtain the supported catalyst. Preferably, the calcination temperature is 400-550℃, and the calcination time is, for example, 2-6 hours.

[0019] As a preferred embodiment of the present invention, the amount of the supported catalyst is 3-10 wt% relative to sucrose-6-ethyl ester, preferably 4-7 wt%.

[0020] As a preferred embodiment of the present invention, the molar ratio of sucrose-6-ethyl ester and hexachlorocyclohexane-2,5-dienone is 1:(3-5), preferably 1:(3-4).

[0021] As a preferred embodiment of the present invention, the solvent is DMF (N,N-dimethylformamide) and / or DMAC (N,N-dimethylacetamide);

[0022] Preferably, the amount of solvent used is 6-12 times the mass of sucrose-6-ethyl ester.

[0023] As a preferred embodiment of the present invention, the reaction adopts a programmed temperature increase, raising the temperature to 70-90°C within 1-3 hours and holding the reaction at that temperature for 2-5 hours.

[0024] As a preferred embodiment of the present invention, after the reaction is completed, the solvent is removed by distillation, and the crude product is purified by recrystallization to obtain sucralose-6-ethyl ester.

[0025] The beneficial effects of this invention are as follows:

[0026] This invention uses hexachlorocyclohexyl-2,5-dienone as a chlorinating agent to produce sucralose-6-ethyl ester in high yield, solving the problems of high safety risks, low product yield, and numerous byproducts associated with traditional synthesis processes. Therefore, the process route of this invention has advantages such as mild reaction conditions, environmental friendliness, high product yield, and simple post-processing. Furthermore, through structural design and optimization of the supported catalyst, the reaction can be promoted at a high conversion rate while suppressing polychlorinated side reactions, thereby improving reaction selectivity. The raw material conversion rate and product selectivity of the method of this invention are both >90%. Detailed Implementation

[0027] The present invention will be further illustrated below with specific embodiments. These embodiments are merely illustrative and do not limit the scope of the invention.

[0028] Unless otherwise specified, all raw materials and reagents used in this invention can be purchased commercially.

[0029] Liquid chromatography analysis conditions for the product: Waters liquid chromatograph, Waters XBridge Amide column, ELSD detector, mobile phase acetonitrile / ammonia water 60 / 40, column temperature 45℃.

[0030] The sources of the instruments and reagents used in the following examples are shown in Table 1 below:

[0031] Table 1

[0032] Instruments and reagents source Specification liquid chromatograph Waters planetary ball mill Qiuzuo Technology XQM-0.4 type sucrose-6-ethyl ester Commercially available, CAS 63648-81-7 >98％ Hexachlorocyclohex-2,5-dienone Commercially available, CAS 599-52-0 >97％

[0033] Unless otherwise specified, all other raw materials and reagents used in the following examples are commercially available.

[0034] The following examples 1-5 and Comparative Example 1 are used to prepare different supported catalysts.

[0035]

Preparation of Example 1

[0036] Take 111.8g of silicon dioxide, soak it in 300mL of 0.1mol / L dilute hydrochloric acid at 20℃ for 2h, wash it repeatedly with deionized water, and dry it at 70℃ to obtain the activated carrier.

[0037] 30g of copper chloride dihydrate, 13.2g of chromium sulfate, and the above-mentioned activated carrier were added to a planetary ball mill and mixed thoroughly. After the mixture was removed, it was calcined at 400℃ for 2 hours, crushed, and shaped to obtain catalyst 1.

[0038]

Preparation of Example 2

[0039] Take 106.9g of 4A molecular sieve, soak it in 300mL of 0.1mol / L dilute hydrochloric acid at 25℃ for 2h, wash it repeatedly with deionized water, and dry it at 75℃ to obtain the activated carrier.

[0040] 35g of copper sulfate pentahydrate, 13.07g of chromium chloride hexahydrate, and the above-mentioned activated carrier were added to a planetary ball mill and mixed thoroughly. After the mixture was removed, it was calcined at 500℃ for 3 hours, crushed, and shaped to obtain catalyst 2.

[0041] [Preparation Example 3]

[0042] Take 161.65g of neutral alumina, soak it in 300mL of 0.1mol / L dilute hydrochloric acid at 25℃ for 2h, wash it repeatedly with deionized water and dry it at 75℃ to obtain the activated carrier.

[0043] 33g of copper acetate, 18.61g of chromium nitrate nonahydrate, and the above-mentioned activated support were added to a planetary ball mill and mixed thoroughly. After the mixture was removed, it was calcined at 450℃ for 4 hours, crushed, and shaped to obtain catalyst 3.

[0044] [Preparation Example 4]

[0045] Take 91.97g of silica, soak it in 300mL of 0.1mol / L dilute hydrochloric acid at 30℃ for 2h, wash it repeatedly with deionized water and dry it at 75℃ to obtain the activated carrier.

[0046] 40g of copper carbonate, 24.1g of chromium chloride hexahydrate, and the above-mentioned activated support were added to a planetary ball mill and mixed thoroughly. After the mixture was removed, it was calcined at 550℃ for 5 hours, crushed, and shaped to obtain catalyst 4.

[0047] [Preparation Example 5]

[0048] Take 133.62g of carbon nanotubes, soak them in 300mL of 0.1mol / L dilute hydrochloric acid at 25℃ for 2h, wash them repeatedly with deionized water, and dry them at 80℃ to obtain the activated carrier.

[0049] 35g of copper sulfate pentahydrate, 21.44g of chromium phosphate hexahydrate, and the above-mentioned activated support were added to a planetary ball mill and mixed thoroughly. After the mixture was extracted, it was calcined at 480℃ for 6 hours, crushed, and shaped to obtain catalyst 5.

[0050] [Prepare Comparison Example 1]

[0051] The catalyst was prepared using the same method as in Example 1, except that chromium sulfate was not added. The resulting catalyst was designated Catalyst D1.

[0052] Examples 1-5 and Comparative Example 1 were used to synthesize sucralose-6-ethyl ester by different schemes.

[0053]

Example 1

[0054] Catalyst 1 (4.61 g), sucrose-6-ethyl ester (115.24 g, 0.3 mol), and hexachlorocyclohexane-2,5-dienone (270.7 g, 0.9 mol) were added to a reactor equipped with a mechanical stirrer, thermocouple, and condenser. Then, 692 g of DMF solvent was added and stirring was started. Subsequently, the thermocouple was turned on to perform a programmed temperature rise, raising the temperature to 70 °C within 1 hour and holding it at that temperature for 5 hours. After the reaction was completed, the solid catalyst was removed by filtration, and the reaction solution was separated. The solvent in the reaction solution was removed by distillation, and the crude product was then thermally crystallized in ethyl acetate to obtain the white solid product, sucrose-6-ethyl ester.

[0055] 1 H NMR (400MHz, CDCl3): δ5.03(d,J=7.0Hz,1H), 4.51(t,J=7.2Hz,2H), 4.34(dd,J=11.2,7.0Hz,1H), 4.14(dd,J=7.2,6.0Hz,1H), 4.09(dd ,J=11.2,6.2Hz,1H),3.97(d,J=7.0Hz,1H),3.62-3.78(m,9H),3.60(dd,J=11.4,7.2Hz,1H),3.38(dd,J=11.4,6.0Hz,1H),2.21(s,3H).

[0056] In this embodiment, the conversion rate of the raw material sucrose-6-ethyl ester was 97.8%, and the selectivity of the product sucralose-6-ethyl ester was 91.7%.

[0057]

Example 2

[0058] Catalyst 2 (6.91 g), sucrose-6-ethyl ester (115.24 g, 0.3 mol), and hexachlorocyclohexane-2,5-dienone (288.75 g, 0.96 mol) were added to a reactor equipped with a mechanical stirrer, thermocouple, and condenser. Then, 925 g of DMF solvent was added and stirring was started. Subsequently, the thermocouple was turned on to perform a programmed temperature increase, raising the temperature to 85 °C within 2 hours and holding it at that temperature for 3 hours. After the reaction was completed, the solid catalyst was removed by filtration, and the reaction solution was separated. The solvent in the reaction solution was removed by distillation, and the crude product was then thermally crystallized in ethyl acetate to obtain the white solid product, sucrose-6-ethyl ester.

[0059] In this embodiment, the conversion rate of the raw material sucrose-6-ethyl ester was 99%, and the selectivity of the product sucralose-6-ethyl ester was 93.6%.

[0060]

Example 3

[0061] Catalyst 3 (3.46 g), sucrose-6-ethyl ester (115.24 g, 0.3 mol), and hexachlorocyclohexane-2,5-dienone (333.87 g, 1.11 mol) were added to a reactor equipped with a mechanical stirrer, thermocouple, and condenser. Then, 1150 g of DMF solvent was added and stirring was started. Subsequently, the thermocouple was turned on to perform a programmed temperature rise, raising the temperature to 80 °C within 1.5 hours and holding it at that temperature for 3 hours. After the reaction was completed, the solid catalyst was removed by filtration, and the reaction solution was separated. The solvent in the reaction solution was removed by distillation, and the crude product was then thermally crystallized in ethyl acetate to obtain the white solid product, sucrose-6-ethyl ester.

[0062] In this embodiment, the conversion rate of the raw material sucrose-6-ethyl ester was 98.5%, and the selectivity of the product sucralose-6-ethyl ester was 92.4%.

[0063]

Example 4

[0064] Catalyst 4 (8.07 g), sucrose-6-ethyl ester (115.24 g, 0.3 mol), and hexachlorocyclohexane-2,5-dienone (360.94 g, 1.2 mol) were added to a reactor equipped with a mechanical stirrer, thermocouple, and condenser. Then, 1380 g of DMF solvent was added and stirring was started. Subsequently, the thermocouple was turned on to perform a programmed temperature increase, raising the temperature to 90 °C within 2.5 hours and holding it at that temperature for 2 hours. After the reaction was completed, the solid catalyst was removed by filtration, and the reaction solution was separated. The solvent in the reaction solution was removed by distillation, and the crude product was then thermally crystallized in ethyl acetate to obtain the white solid product, sucrose-6-ethyl ester.

[0065] In this embodiment, the conversion rate of the raw material sucrose-6-ethyl ester was 99%, and the selectivity of the product sucralose-6-ethyl ester was 91.5%.

[0066]

Example 5

[0067] Catalyst 5 (11.52 g), sucrose-6-ethyl ester (115.24 g, 0.3 mol), and hexachlorocyclohexane-2,5-dienone (451.17 g, 1.5 mol) were added to a reactor equipped with a mechanical stirrer, thermocouple, and condenser. Then, 920 g of DMF solvent was added and stirring was started. Subsequently, the thermocouple was turned on to perform a programmed temperature rise, raising the temperature to 75 °C within 3 hours and holding it at that temperature for 2 hours. After the reaction was completed, the solid catalyst was removed by filtration, and the reaction solution was separated. The solvent in the reaction solution was removed by distillation, and the crude product was then thermally crystallized in ethyl acetate to obtain the white solid product, sucrose-6-ethyl ester.

[0068] In this embodiment, the conversion rate of the raw material sucrose-6-ethyl ester was 96.5%, and the selectivity of the product sucralose-6-ethyl ester was 90.2%.

[0069] Comparative Example 1

[0070] Sucralose-6-ethyl ester was prepared using essentially the same method as in Example 1, except that catalyst 1 was replaced with catalyst D1.

[0071] Post-reaction analysis revealed that the conversion rate of the raw material sucrose-6-ethyl ester was 97.1%, and the selectivity of the product sucralose-6-ethyl ester was 72.3%.

[0072] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing sucralose-6-ethyl ester, characterized in that, This includes the selective chlorination reaction of sucrose-6-ethyl ester and hexachlorocyclohexane-2,5-dienone in a solvent under the action of a supported catalyst to generate sucrose-6-ethyl ester; The supported catalyst is designated as Cu-Cr / X and consists of a Cu main catalyst, a Cr co-catalyst, and an X support. The X support is selected from one or more of activated carbon, carbon nanotubes, molecular sieves, neutral alumina, and silica. The Cu / Cr content ratio in the supported catalyst is 1:(0.3-0.6), based on the molar ratio of metal elements.

2. The method for preparing sucralose-6-ethyl ester according to claim 1, characterized in that, The X carrier is selected from one or more of 4A molecular sieves and silica.

3. The method for preparing sucralose-6-ethyl ester according to claim 1, characterized in that, In the supported catalyst, the Cu / Cr content ratio is 1:(0.3-0.4), calculated as the molar ratio of metal elements.

4. The method for preparing sucralose-6-ethyl ester according to claim 3, characterized in that, In the supported catalyst, the mass of the support is 8-15 times the mass of Cu.

5. The method for preparing sucralose-6-ethyl ester according to claim 4, characterized in that, In the supported catalyst, the mass of the support is 10-14 times the mass of Cu.

6. The method for preparing sucralose-6-ethyl ester according to any one of claims 1-5, characterized in that, The amount of the supported catalyst used is 3-10 wt% relative to sucrose-6-ethyl ester.

7. The method for preparing sucralose-6-ethyl ester according to claim 6, characterized in that, The amount of the supported catalyst used is 4-7 wt% relative to sucrose-6-ethyl ester.

8. The method for preparing sucralose-6-ethyl ester according to any one of claims 1-5, characterized in that, The molar ratio of sucrose-6-ethyl ester to hexachlorocyclohexane-2,5-dienone is 1:(3-5).

9. The method for preparing sucralose-6-ethyl ester according to claim 8, characterized in that, The molar ratio of sucrose-6-ethyl ester to hexachlorocyclohexane-2,5-dienone is 1:(3-4).

10. The method for preparing sucralose-6-ethyl ester according to any one of claims 1-5, characterized in that, The solvent is DMF and / or DMAC.

11. The method for preparing sucralose-6-ethyl ester according to claim 10, characterized in that, The amount of solvent used is 6-12 times the mass of sucrose-6-ethyl ester.

12. The method for preparing sucralose-6-ethyl ester according to any one of claims 1-5, characterized in that, The reaction is carried out using a programmed temperature increase, raising the temperature to 70-90℃ within 1-3 hours and holding the temperature for 2-5 hours.

13. The method for preparing sucralose-6-ethyl ester according to any one of claims 1-5, characterized in that, After the reaction was completed, the solvent was removed by distillation, and the crude product was purified by recrystallization to obtain sucralose-6-ethyl ester.