Preparation method of Advantame

Abstract

The invention belongs to the technical field of organic matter synthesis, and particularly relates to a preparation method of Advantame. The polymerization inhibitor is used before the aspartame is added, so that side reaction can be reduced; tetrahydropyrrole is adopted to catalyze formation of an imine intermediate, side reaction is controlled, and the yield of the product is increased; the reaction temperature for generating the imine intermediate is controlled to be a low temperature of-20 to-10 DEG C, and the side reaction is controlled, so that the reaction is safer and more efficient. According to the present invention, the monatomic dispersion catalyst Pd1 / TiO2 is adopted, palladium is dispersed on the TiO2 skeleton as monatomic, such that the contact area with the catalytic substrate can be increased so as to significantly improve the hydrogenation efficiency, and through the secondary hydrogenation reaction, the limitation and the influence of the water produced during the first hydrogenation reaction process on the reaction can be reduced so as to further improve the yield. The method is simple and easy to implement, few in by-products, high in product purity, high in yield and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing adventitone. Background Art

[0002] Advantame, a derivative of aspartame, is 20,000 times sweeter than sucrose and has a similar structure to neotame. Advantame has a zero energy value and a pure sweetness, similar to sucrose, without an aftertaste. It has a good application prospect in low-sugar or sugar-free foods and beverages. Advantame can be used to partially replace sugars and other high-intensity sweeteners in foods and beverages while maintaining the original taste. Because Advantame can be well compounded with caloric and non-caloric sweeteners, it provides food and beverage companies with the opportunity to reduce calories and lower their sweetener usage costs. In addition, Advantame can be used as a flavor enhancer to enhance the flavor of a variety of products such as dairy products, juices, and mint gum. Advantame is also an excellent tool for masking the odor of functional ingredients.

[0003] At present, there are many reports on the preparation method of edavantin. Chinese invention patent CN111875666A discloses a method for synthesizing edavantin, which uses 3-hydroxy-4-methoxyphenyl acrolein or 3-hydroxy-4-methoxyphenyl propionaldehyde and aspartame to dehydrate and then reduce and hydrogenate to obtain edavantin. However, the use of a dehydrating agent to promote the overall reaction effect in this patent is not ideal. First, the dehydrating agent cannot promote the formation of imines well, and liquids or irregular solids are not easy to remove. When they cannot be reused, they are prone to pollution. Second, the imine formation process itself is a reversible reaction, and a small amount of moisture will still be produced during the hydrogenation reaction, which inhibits the reaction and affects the yield of the reaction. Third, it is impossible to control the polymerization of aldehydes in the imine formation process to form by-products, which affects the conversion rate and the yield of the product. Chinese invention patent CN117586341A discloses a method for synthesizing edavanstatin, which uses metal nickel to catalyze hydrogenation to produce edavanstatin. Because metal nickel is very prone to spontaneous combustion, the operation process is extremely dangerous. In addition, nickel used alone as a catalyst, without a load, will seriously affect the efficiency of hydrogenation due to poor dispersion, thereby affecting the conversion rate of the product. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing Advantine, which is simple and easy to implement, has few by-products, high product purity, high yield, and is green and environmentally friendly.

[0005] The technical solution of the present invention is as follows: The preparation method of Advantame of the present invention comprises the following steps: (1) dissolving 3-hydroxy-4-methoxyphenylacrolein in a solvent of methanol, adding a polymerization inhibitor and tetrahydropyrrole, and then adding aspartame to obtain a mixed solution; (2) adding 4A molecular sieve to the mixed solution of step (1) to react and generate an imine intermediate; (3) first filtering to remove the 4A molecular sieve, and then distilling under reduced pressure to recover the solvent to obtain an imine concentrate; (4) adding solvent methanol to the imine concentrate, then adding hydrogenation catalyst Pd1 / TiO2, and introducing hydrogen to carry out hydrogenation reaction; (5) After the hydrogenation reaction is completed, dehydration adsorption is carried out, and then a secondary hydrogenation reaction is carried out; (6) After the reaction is completed, the solvent methanol is first distilled to recover the concentrated solution, water is added to the concentrated solution for dissolution and recrystallization, and then centrifugation and drying are performed to obtain Advantine.

[0006] Preferably, in step (1), the amount of methanol added is 8-12 times the mass of 3-hydroxy-4-methoxyphenylacrolein.

[0007] Preferably, in step (1), the polymerization inhibitor is hydroquinone, and the amount of the polymerization inhibitor added is 2%-10% of the mass of 3-hydroxy-4-methoxyphenylacrolein. Preferably, in step (1), the amount of tetrahydropyrrole added is 10-12% of the mass of 3-hydroxy-4-methoxyphenylacrolein.

[0008] Preferably, in step (1), the molar ratio of aspartame to 3-hydroxy-4-methoxyphenylacrolein is 1.1:1-1.2:1.

[0009] Preferably, in step (2), the amount of 4A molecular sieve added is 10%-15% of the mass of the mixed solution.

[0010] Preferably, in step (2), the reaction temperature for generating the imine intermediate is -20--10°C, and the reaction time is 20-24h.

[0011] Preferably, in step (4), the same mass of methanol as in step (1) is added.

[0012] Preferably, in step (4), the amount of Pd1 / TiO2 added is 8-10% of the mass of 3-hydroxy-4-methoxyphenylacrolein.

[0013] Preferably, in step (4), the hydrogenation reaction conditions are: hydrogenation pressure is 0.3-0.5 MPa, and reaction temperature is 30-40°C.

[0014] Preferably, in step (5), the dehydration adsorption adopts 4A molecular sieve fixed bed dehydration.

[0015] Preferably, in step (5), the secondary hydrogenation reaction conditions are: hydrogenation pressure is 0.5-0.8 MPa, and reaction temperature is 30-40°C.

[0016] Preferably, in step (6), the dissolution temperature for dissolution and recrystallization is 70-80°C, and then gradually cooled to 0-10°C for crystallization, and the water is deionized water. Dissolution and recrystallization can further purify the product.

[0017] In step (3) and step (6), methanol and tetrahydropyrrole in the solvent are recovered and can be reused.

[0018] Compared with the prior art, the present invention has the following beneficial effects: 1. The method of the present invention is simple and easy to implement, has few by-products, high product purity, high yield, and is green and environmentally friendly.

[0019] 2. In the process of imine formation, by-products are formed due to the self-polymerization of aldehydes. The present invention can reduce side reactions by using an inhibitor before adding aspartame; tetrahydropyrrole is used to catalyze the formation of imine intermediates, control the occurrence of side reactions, and improve the yield of the product; the reaction temperature for generating imine intermediates is controlled to be a low temperature of -20--10°C, which can also control the occurrence of side reactions and make the reaction safer and more efficient.

[0020] 3. The single-atom dispersed catalyst Pd1 / TiO2 used in the present invention has palladium dispersed in the TiO2 skeleton in a single atom, which can increase the contact area with the catalytic substrate, thereby significantly improving the hydrogenation efficiency.

[0021] 4. Both the imine reaction process and the hydrogenation reaction will produce water, which will affect the reaction process. The present invention adopts fixed bed dehydration to promote the reaction in the positive direction. The secondary hydrogenation reaction after fixed bed dehydration can reduce the restriction and influence of the water produced in the first hydrogenation reaction on the reaction, and further improve the yield.

[0022] 5. The present invention recovers the solvent multiple times during the preparation process and reuses it, thereby reducing environmental pollution and sewage treatment costs. DETAILED DESCRIPTION

[0023] The present invention is further described below with reference to the examples. Unless otherwise specified, all raw materials used in the examples are commercially available.

[0024] Example 1 The preparation method of Advantame comprises the following steps: (1) dissolving 3-hydroxy-4-methoxyphenylacrolein in a solvent of methanol, adding a polymerization inhibitor of hydroquinone and tetrahydropyrrole, and then adding aspartame to obtain a mixed solution; The added amount of methanol is 10 times the mass of 3-hydroxy-4-methoxyphenylacrolein, the added amount of hydroquinone is 6% of the mass of 3-hydroxy-4-methoxyphenylacrolein, the added amount of tetrahydropyrrole is 11% of the mass of 3-hydroxy-4-methoxyphenylacrolein, and the molar ratio of aspartame to 3-hydroxy-4-methoxyphenylacrolein is 1.1:1.

[0025] (2) adding 4A molecular sieve to the mixed solution of step (1) to react and generate an imine intermediate; The addition amount of 4A molecular sieve is 12% of the mass of the mixed solution, the reaction temperature for generating the imine intermediate is -15°C, and the reaction time is 22h.

[0026] (3) First, filter to remove the 4A molecular sieve, and then distill under reduced pressure to recover the solvent to obtain an imine concentrate.

[0027] (4) adding an equal mass of the solvent methanol in step (1) to the imine concentrate, then adding a hydrogenation catalyst Pd1 / TiO2, and introducing hydrogen to carry out a hydrogenation reaction; The addition amount of Pd1 / TiO2 is 10% of the mass of 3-hydroxy-4-methoxyphenylacrolein. Pd1 / TiO2 comes from Grace (China) Co., Ltd. The hydrogenation reaction conditions are: hydrogenation pressure of 0.4 MPa and reaction temperature of 35°C.

[0028] (5) After the hydrogenation reaction is completed, a 4A molecular sieve fixed bed is used for dehydration adsorption, and then a secondary hydrogenation reaction is performed; Secondary hydrogenation reaction conditions: hydrogenation pressure is 0.7MPa, reaction temperature is 35℃.

[0029] (6) After the reaction is completed, the solvent methanol is first distilled to recover the concentrated solution, deionized water is added to the concentrated solution, the temperature is maintained at 75°C, and then the temperature is gradually lowered to 5°C for crystallization. After centrifugal drying, Advantine is obtained with a purity of 98.5% and a yield of 98%.

[0030] Example 2 The preparation method of Advantame comprises the following steps: (1) dissolving 3-hydroxy-4-methoxyphenylacrolein in a solvent of methanol, adding a polymerization inhibitor of hydroquinone and tetrahydropyrrole, and then adding aspartame to obtain a mixed solution; The amount of methanol added is 12 times the mass of 3-hydroxy-4-methoxyphenylacrolein, the amount of hydroquinone added is 10% of the mass of 3-hydroxy-4-methoxyphenylacrolein, the amount of tetrahydropyrrole added is 12% of the mass of 3-hydroxy-4-methoxyphenylacrolein, and the molar ratio of aspartame to 3-hydroxy-4-methoxyphenylacrolein is 1.2:1.

[0031] (2) adding 4A molecular sieve to the mixed solution of step (1) to react and generate an imine intermediate; The addition amount of 4A molecular sieve is 15% of the mass of the mixed solution, the reaction temperature for generating the imine intermediate is -10°C, and the reaction time is 20h.

[0032] (3) First, filter to remove the 4A molecular sieve, and then distill under reduced pressure to recover the solvent to obtain an imine concentrate.

[0033] (4) adding an equal mass of the solvent methanol in step (1) to the imine concentrate, and then adding a hydrogenation catalyst Pd1 / TiO2, wherein Pd1 / TiO2 is from Grace (China) Co., Ltd., and introducing hydrogen to carry out a hydrogenation reaction; The addition amount of Pd1 / TiO2 is 10% of the mass of 3-hydroxy-4-methoxyphenylacrolein, and the hydrogenation reaction conditions are: hydrogenation pressure is 0.5MPa, and reaction temperature is 40℃.

[0034] (5) After the hydrogenation reaction is completed, a 4A molecular sieve fixed bed is used for dehydration adsorption, and then a secondary hydrogenation reaction is performed; Secondary hydrogenation reaction conditions: hydrogenation pressure is 0.8MPa, reaction temperature is 40℃.

[0035] (6) After the reaction is completed, the solvent methanol is first distilled to recover the concentrated solution, deionized water is added to the concentrated solution, the temperature is maintained at 70°C, and then the temperature is gradually lowered to 0°C for crystallization. After centrifugal drying, Advantine is obtained with a purity of 98.1% and a yield of 97%.

[0036] Example 3 The preparation method of Advantame comprises the following steps: (1) dissolving 3-hydroxy-4-methoxyphenylacrolein in a solvent of methanol, adding a polymerization inhibitor of hydroquinone and tetrahydropyrrole, and then adding aspartame to obtain a mixed solution; The added amount of methanol is 8 times the mass of 3-hydroxy-4-methoxyphenylacrolein, the added amount of hydroquinone is 2% of the mass of 3-hydroxy-4-methoxyphenylacrolein, the added amount of tetrahydropyrrole is 10% of the mass of 3-hydroxy-4-methoxyphenylacrolein, and the molar ratio of aspartame to 3-hydroxy-4-methoxyphenylacrolein is 1.1:1.

[0037] (2) adding 4A molecular sieve to the mixed solution of step (1) to react and generate an imine intermediate; The addition amount of 4A molecular sieve is 10% of the mass of the mixed solution, the reaction temperature for generating the imine intermediate is -20°C, and the reaction time is 24h.

[0038] (3) First, filter to remove the 4A molecular sieve, and then distill under reduced pressure to recover the solvent to obtain an imine concentrate.

[0039] (4) Add an equal mass of methanol solvent from step (1) to the imine concentrate, and then add a hydrogenation catalyst Pd1 / TiO 2， Pd1 / TiO2 comes from Grace (China) Co., Ltd., and hydrogen is introduced to carry out hydrogenation reaction; The addition amount of Pd1 / TiO2 is 8% of the mass of 3-hydroxy-4-methoxyphenylacrolein, and the hydrogenation reaction conditions are: hydrogenation pressure is 0.3MPa, and reaction temperature is 30℃.

[0040] (5) After the hydrogenation reaction is completed, a 4A molecular sieve fixed bed is used for dehydration adsorption, and then a secondary hydrogenation reaction is performed; Secondary hydrogenation reaction conditions: hydrogenation pressure is 0.5MPa, reaction temperature is 30℃.

[0041] (6) After the reaction is completed, the solvent methanol is first distilled to recover the concentrated solution, deionized water is added to the concentrated solution, the temperature is maintained at 80°C, and then the temperature is gradually lowered to 10°C for crystallization. After centrifugal drying, Advantine is obtained with a purity of 99.2% and a yield of 99%.

[0042] Comparative Example 1 Referring to Example 1, the difference is that no inhibitor is added in step (1), and the purity of the obtained Advantamine is 96.5%, and the yield is 71%.

[0043] Comparative Example 2 Referring to Example 1, except that tetrahydropyrrole was not added in step (1), the purity of the obtained Advantame was 82.4% and the yield was 97%.

[0044] Comparative Example 3 Referring to Example 1, the difference is that the reaction temperature for generating the imine intermediate in step (2) is 10° C., and the purity of the obtained Advantine is 97.5%, and the yield is 89%.

[0045] Comparative Example 4 Referring to Example 1, the difference is that the hydrogenation catalyst is palladium carbon, and the purity of the obtained Advantamine is 97.8%, and the yield is 90%.

[0046] Comparative Example 5 Referring to Example 1, except that the secondary hydrogenation reaction of step (5) was not performed, the purity of the obtained Advantame was 98.0% and the yield was 92%.

Claims

1. A method for preparing Advantame, characterized in that: The following steps are involved: (1) dissolving 3-hydroxy-4-methoxyphenylpropenal in methanol as a solvent, adding a polymerization inhibitor and tetrahydropyrrole, and then adding aspartame to obtain a mixed solution, wherein the molar ratio of aspartame to 3-hydroxy-4-methoxyphenylpropenal is 1.1:1-1.2:1; (2) adding 4A molecular sieve to the mixed solution of step (1) to react to generate an imine intermediate, wherein the reaction temperature for generating the imine intermediate is -20 to 10°C; (3) first filtering to remove the 4A molecular sieve, and then distilling under reduced pressure to recover the solvent to obtain an imine concentrate; (4) adding solvent methanol to the imine concentrate, then adding hydrogenation catalyst Pd1 / TiO2, and introducing hydrogen to carry out hydrogenation reaction; (5) After the hydrogenation reaction is completed, dehydration adsorption is carried out, and then a secondary hydrogenation reaction is carried out; (6) After the reaction is completed, the solvent methanol is first distilled to recover the concentrated solution, water is added to the concentrated solution for dissolution and recrystallization, and then centrifugation and drying are performed to obtain Advantine.

2. The method for preparing Advantame according to claim 1, characterized in that: In step (1), the amount of methanol added is 8-12 times the mass of 3-hydroxy-4-methoxyphenylacrolein.

3. The method for preparing Advantame according to claim 1, characterized in that: In step (1), the polymerization inhibitor is hydroquinone, and the amount of the polymerization inhibitor added is 2%-10% of the mass of 3-hydroxy-4-methoxyphenylacrolein.

4. The method for preparing Advantame according to claim 1, characterized in that: In step (1), the amount of tetrahydropyrrole added is 10-12% of the mass of 3-hydroxy-4-methoxyphenylacrolein.

5. The method for preparing Advantame according to claim 1, characterized in that: In step (2), the amount of 4A molecular sieve added is 10%-15% of the mass of the mixed solution.

6. The method for preparing Advantame according to claim 1, characterized in that: In step (2), the reaction time for generating the imine intermediate is 20-24 hours.

7. The method for preparing Advantame according to claim 1, characterized in that: In step (4), the amount of Pd1 / TiO2 added is 8-10% of the mass of 3-hydroxy-4-methoxyphenylacrolein.

8. The method for preparing Advantame according to claim 1, characterized in that: In step (4), the hydrogenation reaction conditions are: hydrogenation pressure is 0.3-0.5 MPa, and reaction temperature is 30-40°C.

9. The method for preparing Advantame according to claim 1, characterized in that: In step (5), the secondary hydrogenation reaction conditions are: hydrogenation pressure is 0.5-0.8 MPa, and reaction temperature is 30-40°C.