Preparation method of neotame
By using a Raney nickel catalyst and acetic acid in a methanol solvent for hydrogenation reduction, combined with pH adjustment and activated carbon purification, the problem of neotame preparation caused by the easy agglomeration of palladium on carbon catalyst was solved, and efficient and low-cost neotame production was achieved.
Patent Information
- Application Number
- CN202511153503.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-18
- Publication Date
- 2025-12-19
AI Technical Summary
In existing technologies, palladium-on-carbon catalysts are prone to agglomeration, which leads to a decrease in catalytic efficiency and incomplete reaction during neotame preparation, increases aspartame consumption and side reactions, results in low product purity, makes separation and purification difficult, and increases production costs.
A hydrogenation reduction reaction was carried out in methanol solvent using a Raney nickel catalyst and acetic acid. By adjusting the pH value, crude neotame product was precipitated. Combined with activated carbon purification, the transesterification side reactions and impurity formation were reduced, thereby improving the reaction conversion rate and product purity.
It improves the reaction conversion rate of neotame, reduces raw material consumption and production costs, simplifies the separation and purification process, and enhances product purity.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of compound synthesis, in particular to a preparation method of neotame. BACKGROUND
[0002] Neotame (NTM) is a derivative of aspartame, a dipeptide sweetener, and its chemical name is N-〔N-(3,3-dimethylbutyl)-L-α-aspartyl〕-L-phenylalanine 1-methyl ester. As a new type of dipeptide high-fold sweetener, neotame is a non-nutritive zero-calorie sweetener, with a sweetness of 7000-13000 times that of sucrose and 30-60 times that of aspartame, and a unit sweetness heat value of <0.2J, which is much lower than that of sucrose with the same sweetness. Its in vivo absorption is less than 10%, and its own and metabolic product de-esterified neotame can be rapidly and completely excreted without accumulation, without increasing blood glucose and affecting insulin concentration and blood glucose control, and is suitable for people such as diabetic patients. It is also suitable for patients with phenylketonuria who cannot eat aspartame.
[0003] In some scenarios, when 3,3-dimethylbutanal and aspartame are used to generate neotame under the catalysis of palladium-carbon, the palladium nanoparticles in the palladium-carbon catalyst are prone to agglomeration due to impurities in the reaction system, temperature fluctuations or local concentration being too high, resulting in a sharp decrease in the number of active sites and a significant decrease in catalytic efficiency with the progress of the reaction. This makes the reaction difficult to proceed fully, not only exacerbating the excessive consumption of aspartame (which needs to be maintained by increasing the amount of feed), but also increasing the difficulty of subsequent separation and purification due to the presence of unreacted raw materials, directly leading to a decrease in product purity. In addition, when the palladium-carbon catalyst catalyzes the condensation of aldehyde and amine and the hydrogenation reaction, side reactions may occur, such as the condensation of 3,3-dimethylbutanal itself and the accidental hydrogenation of the ester group in the aspartame molecule, generating non-target impurities. These by-products have similar physicochemical properties to neotame, further increasing the complexity of the separation and purification process, while causing ineffective loss of raw materials and increasing production costs. As a result, due to the low catalytic efficiency of the palladium-carbon catalyst, aspartame cannot be completely reacted, resulting in excessive consumption of aspartame and the occurrence of side reactions, causing material loss, increasing production costs, and low product purity. SUMMARY
[0004] In order to solve the technical problems of material loss, increased production costs, and low product purity in the preparation of neotame, the purpose of the present application is to provide a preparation method of neotame, and the technical scheme adopted is as follows: The embodiment of the present application discloses a preparation method of neotame, comprising: adding 3,3-dimethylbutanal, aspartame, acetic acid and Raney nickel catalyst into a methanol solvent to obtain a first mixed solution, introducing hydrogen into the first mixed solution to perform a hydrogenation reduction reaction, and obtaining a second mixed solution after the hydrogenation reduction reaction is completed, wherein the acetic acid is used to inhibit a transesterification side reaction caused by the methanol solvent; performing vacuum distillation on the second mixed solution, adding an alkaline regulator to adjust the pH value of the second mixed solution, and precipitating a neotame crude product, and the neotame crude product is refined and purified to obtain neotame.
[0005] Optionally, the content of Ni in the Raney nickel catalyst is greater than or equal to 90%.
[0006] Optionally, the molar ratio of aspartame to 3,3-dimethylbutanal is 1:0.95 to 1:1.05.
[0007] Optionally, the molar ratio of the Raney nickel catalyst to 3,3-dimethylbutanal is 0.05:1 to 0.25:1.
[0008] Optionally, the molar ratio of the sodium bicarbonate to the acetic acid is 1:0.8 to 1:0.9.
[0009] Optionally, the pH value of the second mixed solution is adjusted to 7.5 to 8.5 by adding the alkaline regulator after the vacuum distillation of the second mixed solution, so as to precipitate the neotame crude product.
[0010] Optionally, the hydrogenation pressure for introducing hydrogen into the first mixed solution after the condensation reaction to perform the hydrogenation reduction reaction is 0.8 MPa to 1.0 MPa, and the hydrogenation temperature is 30 DEG C to 45 DEG C.
[0011] Optionally, the method for precipitating the neotame crude product by adding the alkaline regulator to adjust the pH value of the second mixed solution after the vacuum distillation of the second mixed solution comprises the following steps: performing vacuum distillation on the second mixed solution to recover methanol by distillation, adding the alkaline regulator and soft water after the distillation is completed, stirring, cooling and centrifugation, and obtaining a neotame initial product; adding the neotame initial product into anhydrous ethanol to remove an odor, and performing freezing crystallization, cooling and centrifugation to obtain the neotame crude product.
[0012] Optionally, the method for obtaining neotame by refining and purifying the neotame crude product comprises the following steps: adding the neotame crude product, activated carbon and soft water into ethanol, uniformly stirring, heating for refinement, filtering, cooling and centrifugation, and obtaining neotame.
[0013] Optionally, the amount of the activated carbon added is 0.5% to 0.8% of the amount of the neotame crude product.
[0014] By the technical scheme disclosed by the embodiment of the present application, the Raney nickel catalyst is used to catalyze the condensation reaction of 3,3-dimethylbutyraldehyde, aspartame and acetic acid, and the high catalytic activity can promote the condensation reaction to proceed fully, reduce the material loss caused by incomplete reaction of aspartame, and in the hydrogenation reduction reaction, hydrogen gas is used as a reducing agent to promote the conversion of the intermediate product, improve the overall reaction conversion rate, and reduce the raw material consumption. And the acetic acid can inhibit the transesterification side reaction caused by the methanol solvent, reduce the generation of non-target ester impurities, reduce the difficulty of subsequent separation and purification, and reduce the production cost. At the same time, the Raney nickel catalyst has high selectivity for the target reaction, which can reduce the side reactions such as self-condensation of 3,3-dimethylbutyraldehyde, and further improve the purity of neotame product. And using methanol as the solvent, the solubility of methanol to aspartame and the intermediate product is slightly better than that of ethanol, which helps to improve the contact opportunity of the reactants, so that the reaction can proceed faster or more completely, and the material loss is further reduced. In addition, by adjusting the pH value by the alkaline adjusting agent, the problem that the carboxyl (-COOH) in the neotame molecule is protonated in the acidic environment to hinder the crystallization of neotame is avoided, and the problem that the hydrolysis side reaction of neotame or aspartame residue may be caused by the acidic condition is avoided, and under the alkaline condition, the neotame is fully converted into the free state, which can improve the crystallization efficiency of the neotame crude product and the product purity. DETAILED DESCRIPTION
[0015] In order to further illustrate the technical means and effects adopted by the present application to achieve the predetermined object, the specific embodiments, structures, features and effects of the preparation method of neotame according to the present application are described in detail as follows. In the following description, different "one embodiment" or "another embodiment" do not necessarily refer to the same embodiment. In addition, the specific features, structures or characteristics in one or more embodiments can be combined in any suitable form.
[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. The specific embodiments of the preparation method of neotame provided by the present application are specifically described below.
[0017] The preparation method of neotame disclosed by the embodiment of the present application comprises: adding 3,3-dimethylbutyraldehyde, aspartame, acetic acid and Raney nickel catalyst into a methanol solvent to obtain a first mixed solution, introducing hydrogen into the first mixed solution to perform a hydrogenation reduction reaction, and obtaining a second mixed solution after the hydrogenation reduction reaction is completed, wherein the acetic acid is used to inhibit the transesterification side reaction caused by the methanol solvent; after the second mixed solution is subjected to vacuum distillation, a basic adjusting agent is added to adjust the pH value of the second mixed solution, and a neotame crude product is precipitated, and the neotame crude product is refined and purified to prepare neotame.
[0018] Compared with the prior art, the embodiment of the present application has the following beneficial effects: (1) The condensation reaction of 3,3-dimethylbutanal and aspartame is catalyzed by Raney nickel catalyst, which has high catalytic activity and can promote the condensation reaction to proceed fully, reducing the loss of aspartame due to incomplete reaction.
[0019] (2) In the hydrogenation reduction reaction, hydrogen gas acts as a reducing agent to promote the conversion of intermediate products, improve the overall reaction conversion rate, and reduce raw material consumption. Acetic acid can inhibit the transesterification side reaction caused by methanol solvent, reduce the generation of non-target ester impurities, reduce the difficulty of subsequent separation and purification, and reduce production cost.
[0020] (3) The Raney nickel catalyst has high selectivity for the target reaction, which can reduce the condensation of 3,3-dimethylbutanal itself and other side reactions, further improving the purity of neotame product.
[0021] (4) Using methanol as the solvent, methanol generally has slightly better solubility than ethanol for aspartame and reaction intermediates, which helps to improve the contact opportunity of reactants, making the reaction proceed faster or more completely, and further reducing material loss.
[0022] (5) By adjusting the pH value with an alkaline adjusting agent, the problem of hindering neotame crystallization caused by protonation of the carboxyl group (-COOH) in the neotame molecule in an acidic environment is avoided, and the problem of hydrolysis side reaction of neotame or aspartame residues caused by acidic conditions is also avoided. Under alkaline conditions, neotame is fully converted to free state, which can improve the crystallization efficiency of neotame crude product and product purity.
[0023] Further, as an optional embodiment of the present application, the following steps are specifically included: (a) Dissolve 3,3-dimethylbutanal and aspartame in a methanol solvent, and then pass hydrogen gas into the first mixed solution obtained after adding Raney nickel catalyst and acetic acid. Under the catalysis of Raney nickel catalyst and acetic acid, 3,3-dimethylbutanal and aspartame undergo condensation reaction in the methanol solvent to obtain a first mixed solution. Acetic acid is used to inhibit the transesterification side reaction caused by methanol solvent.
[0024] (b) Perform hydrogenation reduction reaction on the first mixed solution in step (a), and after the hydrogenation reduction reaction is completed, a second mixed solution is obtained.
[0025] (c) Perform suction filtration and vacuum distillation on the second mixed solution obtained in step (b) to recover methanol and recover Raney nickel catalyst. After the distillation is completed, add an alkaline adjusting agent, stir with soft water, cool, and centrifuge to obtain a neotame primary product.
[0026] (d) After the vacuum distillation of the second mixed solution in step (c) is completed, add the neotame primary product to anhydrous ethanol to remove odor, and then freeze crystallize, cool, and centrifuge to obtain a neotame crude product.
[0027] (e) adding the neotame crude product, activated carbon and soft water obtained in step (d) into ethanol, stirring uniformly, heating for purification, filtering, cooling, centrifuging to obtain neotame.
[0028] Specifically, the embodiment of the present application adds methanol, aspartame, 3,3-dimethylbutanal, acetic acid and Raney nickel catalyst into the hydrogenation kettle, and hydrogen is introduced into the obtained first mixed solution to carry out hydrogenation reduction reaction. The addition of acetic acid in the embodiment of the present application can maintain the first mixed solution in an acidic environment, which can provide a weak acid environment and can inhibit or reduce the transesterification side reaction caused by the methanol solvent, that is, the methoxy group in the methanol molecule may replace the group in the original ester group to generate non-target ester impurities. The addition of acetic acid can provide a stable weak acid environment (pH value is usually maintained at 3.5-5.0), which can enhance the stability of the ester group through protonation: the hydrogen ion dissociated from acetic acid combines with the oxygen atom in the ester group to form a more stable charged intermediate, reducing the nucleophilic reactivity of the ester group, thereby reducing the probability of attack of the methanol molecule on the ester group, inhibiting the occurrence of transesterification side reaction from the root, reducing the generation of impurities, making more raw materials convert to target product neotame, and thus improving the yield of neotame. At the same time, due to the reduction of impurity content, it is easier to obtain high-purity crude product in the subsequent separation and purification process. In addition, the weak acid environment has good adaptability with the catalytic activity requirement of Raney nickel. Raney nickel has higher catalytic selectivity for hydrogenation reduction reaction under neutral to weak acidic conditions, and can more efficiently promote the combination of imine intermediate generated by condensation reaction with hydrogen, and directional conversion into the amino structure of neotame. The stable weak acid environment provided by acetic acid can avoid the passivation of nickel active sites on the surface of the catalyst (such as the formation of nickel hydroxide and other inert substances) due to excessive alkalinity of the system, and can also prevent the corrosion of the catalyst skeleton or the dissolution of nickel particles caused by excessive acidity (such as the use of strong acid). This effective protection of the activity of the catalyst enables Raney nickel to maintain high catalytic efficiency at a lower dosage, reducing the need for excessive addition due to insufficient catalyst activity, thereby reducing the amount of Raney nickel used and saving production costs.
[0029] Further, after the hydrogenation reduction reaction is completed, the second mixed solution is subjected to suction filtration and reduced pressure distillation to recover methanol and Raney nickel catalyst. After recovery through suction filtration, the Raney nickel catalyst can be used again for hydrogenation reduction reaction, thereby reducing the consumption cost of palladium-carbon catalyst and improving the utilization rate of resources. The reduced pressure distillation can recover the methanol solvent. Since methanol is usually used as a reaction medium in the reaction, the recovered methanol can be reused in the condensation reaction of aspartame and 3,3-dimethylbutyl aldehyde after purification treatment, thereby reducing the amount of methanol to be purchased and realizing the recycling of the solvent. In addition, after the Raney nickel catalyst is removed through suction filtration, the solid catalyst can be prevented from remaining in the reaction solution, thereby preventing interference with the subsequent process of adjusting the pH value to precipitate the neotame crude product and reducing the possibility of introducing impurities. After the methanol is removed through reduced pressure distillation, the concentration of effective components in the reaction solution is increased, so that the subsequent addition of an alkaline adjusting agent to adjust the pH value can make the precipitation of the neotame crude product more complete, thereby facilitating the improvement of the purity of neotame.
[0030] Further, after the reduced pressure distillation is completed, the embodiment of the present application adds an alkaline substance and soft water to react to adjust the pH value of the residual liquid to precipitate a neotame primary product. The neotame primary product is added to anhydrous ethanol to remove odor, crystallized, cooled, and centrifuged to obtain a neotame crude product. The addition of the alkaline adjusting agent can change the pH value of the residual liquid, so that the neotame reaches the critical point of solubility in a suitable pH environment, thereby rapidly and centrally precipitating the crude product. The soft water can avoid the interference of impurities in water with the reaction system, reduce the loss of products caused by the side reactions of calcium ions and magnesium ions in hard water with the alkaline substance or neotame, and further improve the precipitation rate and purity of the crude product. In addition, after the reduced pressure distillation, trace amounts of methanol, unreacted 3,3-dimethylbutyl aldehyde, and other low-boiling-point substances may form odor, which affects the sensory of the product. The anhydrous ethanol as a polar solvent can effectively dissolve these volatile impurities, which are removed together with the ethanol, thereby completely eliminating the odor. In addition, the neotame has a certain solubility in anhydrous ethanol, and part of the low-polarity by-products (such as a small amount of dimers generated in the condensation reaction) have low solubility in ethanol, which can be preliminarily separated by filtration during the dissolution stage. During the cooling and crystallization, the neotame molecules preferentially arrange in an orderly manner to form crystals, and the unsolved impurities remain in the mother liquor. After centrifugal separation, the impurity content in the crude product can be greatly reduced, thereby improving the purity of the final product.
[0031] Finally, the obtained neotame crude product, activated carbon and soft water are added into ethanol, stirred uniformly, refined by heating, filtered, cooled and centrifuged to obtain neotame. Specifically, 1.5-1.8 times the volume of anhydrous ethanol (or 95% ethanol) is added as a solvent based on the mass of the neotame crude product, and 0.5%-0.8% of activated carbon (preferably food-grade powdered activated carbon with strong adsorption capacity) and 10%-15% of soft water (deionized water to reduce the polarity of the system and promote the dissolution of impurities) are added based on the mass of the neotame crude product. Add ethanol to the reaction kettle or refining container, start stirring (control the stirring speed at 200-300 r / min), and slowly add the neotame crude product, activated carbon and soft water in turn, stir until the material is completely dispersed, and form a uniform suspension to avoid agglomeration of activated carbon or deposition of crude product. Under stirring, the temperature of the system is raised to 60-70°C by jacket heating (too high a temperature may cause partial decomposition of neotame, and too low a temperature will affect the impurity dissolution efficiency), and the temperature is maintained for 60-80 minutes. The solubility of ethanol is increased at high temperature, which promotes the complete dissolution of neotame; the activated carbon is fully contacted with the solution under stirring, adsorbing pigments, small molecule impurities and residual odor substances. Then, after filtering, cooling and centrifuging, the crystals obtained by centrifugation are washed with a small amount of cold ethanol (0-5°C) for 2-3 times to remove the surface residual mother liquor impurities, and then dehydrated by centrifugation to obtain high-purity neotame wet product, which can be subsequently vacuum dried to obtain the finished product.
[0032] Further, as an optional embodiment of the present application, the content of Ni in the Raney nickel catalyst is ≥90%. In this way, the content of nickel above 90% can ensure that there are sufficient active sites in the reaction system, accelerate the dissociation of hydrogen molecules and the adsorption and conversion of intermediates, thereby increasing the reaction rate and reducing the overall time consumption. And the Raney nickel catalyst with a content of ≥90% can more accurately catalyze the hydrogenation reaction of imine groups, reduce the generation of by-products, and further improve the purity of neotame in cooperation with acetic acid.
[0033] Further, as an optional embodiment of the present application, the molar ratio of aspartame to 3,3-dimethylbutanal is 1:0.95 to 1:1.05. In this way, the approximate quantitative reaction of the two can be achieved, avoiding the waste caused by excessive excess of a raw material, and the range of 1:0.95-1:1.05 can ensure sufficient reaction of the two, improving the atom economy of the raw material. In addition, this ratio can reduce side reactions caused by the excess of a raw material. For example, when aspartame is excessive, its molecules may undergo self-condensation or further reaction with reaction intermediates to generate complex impurities; when 3,3-dimethylbutanal is excessive, it is prone to self-polymerization to generate aldehyde polymer impurities. Controlling the ratio of the two to be close to 1:1 can minimize the probability of such side reactions, and the effect of acetic acid in inhibiting the ester exchange side reaction forms a synergy, further improving the purity of neotame. And this ratio range can reduce the subsequent purification pressure on the premise of ensuring complete reaction. Taking the molar ratio of 1:1 as an example, at this time aspartame and 3,3-dimethylbutanal are almost completely converted into imine intermediates, and after hydrogenation reduction, the crude yield of neotame can reach more than 90%.
[0034] Further, as an optional embodiment of the present application, the molar ratio of Raney nickel catalyst to 3,3-dimethylbutanal is 0.05:1 to 0.25:1. In this way, this ratio range can not only avoid incomplete reaction caused by insufficient Raney nickel catalyst (such as when the ratio is less than 0.03:1, the conversion rate of imine intermediates may be less than 85%), but also prevent excessive hydrogenation and other side reactions caused by excessive active sites. In addition, excessive Raney nickel may adsorb part of the reaction products, or cause side reactions due to excessively high surface activity (such as excessive reduction of aldehyde groups to alcohol groups), and a ratio of 0.05:1 to 0.25:1 can make the catalyst fully participate in the target reaction while reducing side reaction interference. Taking the molar ratio of 0.2:1 as an example, at this time the content of alcohol by-products in the neotame generated by the hydrogenation reaction can be controlled to be less than 0.5%, while when the ratio increases to 0.4:1, the content of by-products may increase to more than 1.2%, significantly affecting the purity of the product.
[0035] Further, as an optional embodiment of the present application, the basic adjusting agent is sodium bicarbonate, and the molar ratio of sodium bicarbonate to acetic acid is 1:0.8 to 1:0.9.
[0036] Further, as an optional embodiment of the present application, the second mixed solution is subjected to vacuum distillation, and then a basic regulator is added to adjust the pH value of the second mixed solution to 7.5-8.5 to precipitate the neotame crude product. The neotame is an amphoteric molecule (containing carboxyl and amino groups), and the isoelectric point (pI) thereof is generally between pH 5-6. Under an acidic condition (pH < pI), the neotame exists in the form of a cation (-NH3+), is easily dissolved in water, and is difficult to be crystallized and precipitated. Under a neutral to weakly alkaline condition (pH > pI), the carboxyl is ionized to -COO-, the molecule is electrically neutral (free state), and the solubility is the lowest, which is beneficial to crystallization. The addition of the basic regulator to increase the pH value to 7.5-8.5 can convert the neotame into the free state, and significantly improve the crystallization efficiency and the product purity.
[0037] Further, as an optional embodiment of the present application, the hydrogenation pressure for the hydrogenation reduction reaction of the first mixed solution subjected to the condensation reaction is 0.8-1.0 MPa, and the hydrogenation temperature is 30-45°C. In this way, the hydrogen pressure of 0.8-1.0 MPa can provide sufficient hydrogen source for the reaction, promote the dissolution of hydrogen in the liquid phase and the combination with the active sites of Raney nickel catalyst, and accelerate the hydrogenation reaction of imine groups; and the temperature of 30-45°C can activate the activity of the catalyst (avoid the slow reaction rate at low temperature) and ensure the reaction under mild conditions. For example, under the above parameters, the conversion rate of imine intermediate can reach more than 99% in 2-3 hours, which is nearly half of the reaction time (85% conversion rate in 5 hours) under the condition of 0.5 MPa and 25°C, and greatly improves the production efficiency. In addition, the above range can effectively reduce excessive hydrogenation and impurity generation. When the temperature is higher than 45°C, the activity of Raney nickel can be too strong to cause the excessive reduction of aldehyde groups to alcohol groups (for example, 3,3-dimethylbutanal is reduced to 3,3-dimethylbutanol), or initiate the hydrogenation decomposition of aspartame ester groups; and when the pressure is higher than 1.0 MPa, the solubility of hydrogen in the solvent is too high, which can aggravate the occurrence of side reactions. The combination of the mild temperature of 30-45°C and the pressure of 0.8-1.0 MPa can control the content of alcohol by-products to be less than 0.3%, which is much lower than 1.0% under the condition of 50°C and 1.2 MPa, and significantly improves the purity of the neotame crude product.
[0038] Further, as an optional embodiment of the present application, the second mixed solution is subjected to reduced pressure distillation, and then a basic regulator is added to adjust the pH value of the second mixed solution to precipitate the neotame crude product, comprising: the second mixed solution is subjected to reduced pressure distillation to recover methanol by distillation, and then a basic regulator and soft water are added to stir, cool, and centrifuge to obtain a neotame primary product; the neotame primary product is added to anhydrous ethanol to remove odor, and then crystallization, cooling, and centrifugation are performed after the reduced pressure distillation to obtain the neotame crude product. In this way, methanol and the catalyst are recovered specifically, the solvent loss is reduced, recycling is achieved, and the production cost is reduced; after the pH value is adjusted by the basic regulator, the neotame primary product is precipitated preferentially by cooling and centrifugation, the unreacted raw materials and polar impurities are preliminarily separated, and the anhydrous ethanol can be dissolved to deeply remove the residual low-boiling-point odor substances (such as unreacted aldehydes) and nonpolar impurities, thereby significantly improving the product purity and the neotame crude product yield (which can be more than 90%).
[0039] Further, as an optional embodiment of the present application, the neotame crude product is refined and purified to obtain neotame, comprising: the neotame crude product, activated carbon, and soft water are added to ethanol, uniformly stirred, heated for refinement, filtered, cooled, and centrifuged to obtain neotame. In this way, the activated carbon can efficiently adsorb the pigments, residual odor substances, and trace organic impurities in the neotame crude product, the mixed system of soft water and ethanol can dissolve part of the polar impurities, and the impurities can be removed after filtration to improve the purity of the neotame product. The heating refinement can promote the neotame to be fully dissolved, the cooling crystallization can form regular crystals to reduce impurity wrapping, and the product stability can be improved.
[0040] Further, as an optional embodiment of the present application, the amount of activated carbon added is 0.5%-0.8% of the amount of the neotame crude product. In this way, this ratio can ensure that the activated carbon fully contacts and adsorbs the pigments, odor substances, and trace impurities in the crude product, and the impurities will not be left due to insufficient amount, and the activated carbon will not be saturated or unnecessarily adsorb the neotame due to excessive amount, thereby ensuring the purification effect. Embodiment 1:
[0041] (a) 500 ml of methanol, 100 g of 3,3-dimethylbutanal, and 100 g of aspartame were added to a hydrogenation kettle for stirring and dissolution, and then 25 g of Raney nickel catalyst (Ni content ≥ 90%) and acetic acid were added to obtain a first mixed solution.
[0042] (b) hydrogen was introduced into the hydrogenation kettle with the first mixed solution in step (a) until the kettle pressure in the hydrogenation kettle was 0.9 MPa to perform a hydrogenation reduction reaction for 10 h; the acetic acid can inhibit the ester exchange side reaction caused by the methanol solvent; and after the hydrogenation reduction reaction was completed, a second mixed solution was obtained.
[0043] (c) The second mixed solution obtained in step (b) is subjected to suction filtration and reduced pressure distillation to recover methanol and recover the Raney nickel catalyst, after the end of the distillation, 8.0 g of sodium bicarbonate and 450 ml of soft water are added, and the mixture is stirred for 30 min, and then cooled, centrifuged, to obtain the neotame primary product.
[0044] (d) The neotame primary product obtained in step (c) is added to anhydrous ethanol to remove odor, and then subjected to freezing crystallization, cooling, and centrifugation, to obtain the neotame crude product.
[0045] (e) The neotame crude product obtained in step (d), activated carbon, and soft water are added to ethanol, and the mixture is stirred uniformly, heated, refined, filtered, cooled, and centrifuged, to obtain neotame.
[0046] Through detection, the yield of neotame is 85.7%, and the purity is 99.76%. Example 2:
[0047] In order to study the effects of different solvents, different proportions of acetic acid and aspartame, and sodium bicarbonate and aspartame on the yield and purity of the product neotame, the present embodiment of the application selects solvents, different proportions of acetic acid and aspartame, and sodium bicarbonate and aspartame for experiments, and the other operation processes are the same as those in Example 1.
[0048] First, the present embodiment of the application first fixes the molar ratio of aspartame and 3,3-dimethylbutanal to be 1:1, and both aspartame and 3,3-dimethylbutanal are used in an amount of 100 g, the Raney nickel catalyst is used in an amount of 25 g, the molar ratio of acetic acid to aspartame is 1:4, acetic acid is used in an amount of 25 g, and the molar ratio of sodium bicarbonate to aspartame is 1:5, and sodium bicarbonate is used in an amount of 20 g. Under the above amounts, the differences between the reaction temperature requirement, reaction time, and hydrogenation pressure of 3,3-dimethylbutanal and aspartame under the catalysis of the Raney nickel catalyst in the methanol solvent and the ethanol solvent are analyzed.
[0049] Table 1 Reaction parameters of 3,3-dimethylbutanal and aspartame under the catalysis of the Raney nickel catalyst in the methanol solvent and the ethanol solvent
[0050] As can be seen from Table 1, the reaction temperature, reaction time, and hydrogenation pressure of 3,3-dimethylbutanal, aspartame, and the Raney nickel catalyst in methanol are all better than those in ethanol, therefore, the present embodiment of the application selects methanol as the solvent to improve the reaction efficiency and reduce the hydrogenation conditions.
[0051] Secondly, the methanol solvent is used in the embodiment of the present application, and 3, 3 dimethylbutyl aldehyde is fixed at 100g, Raney nickel catalyst is fixed at 25g, and sodium bicarbonate is fixed at 20g, the influence of acetic acid and aspartame on the yield and purity of neotame in different proportions is studied.
[0052] Table 2 Purity and yield of neotame
[0053] From table 2, when the molar ratio of acetic acid and aspartame is 1:4, the yield of neotame reaches 85.7%, and the purity reaches 99.62%, which is better.
[0054] Finally, the methanol solvent is used in the embodiment of the present application, and 3, 3 dimethylbutyl aldehyde is fixed at 100g, Raney nickel catalyst is fixed at 25g, and acetic acid is fixed at 25g, the influence of sodium bicarbonate and aspartame on the yield and purity of neotame in different proportions is studied.
[0055] Table 3 Purity and yield of neotame
[0056] From table 3, when the molar ratio of sodium bicarbonate and aspartame is 1:6, the yield of neotame reaches 85.82%, and the purity reaches 99.76%, which is better.
[0057] From the above analysis, when the methanol is used as the solvent, the molar ratio of acetic acid and aspartame is 1:4, and the molar ratio of sodium bicarbonate and aspartame is 1:6, the yield and purity of neotame reach the optimum.
[0058] In summary, the preparation method of neotame provided by the present application can effectively improve the yield and purity of the product by reasonably controlling the reaction conditions and material ratio, and reduce the production cost. It should be noted that the above-mentioned embodiment sequence of the present application is only for description, and does not represent the advantages and disadvantages of the embodiments. The described process does not necessarily require the specific order or continuous order shown to achieve the desired results. In some embodiments, multitasking and parallel processing are also possible or may be advantageous.
[0059] Each embodiment in the specification is described in a progressive manner, and the same or similar parts between each embodiment can be referred to each other, and each embodiment mainly describes the difference from other embodiments.
Claims
1. A production method for improving the quality of neotame, characterized in that: include: 3,3-Dimethylbutyraldehyde, aspartame, acetic acid, and Raney nickel catalyst were added to methanol solvent to obtain a first mixed solution. Hydrogen gas was introduced into the first mixed solution to carry out a hydrogenation reduction reaction. After the hydrogenation reduction reaction was completed, a second mixed solution was obtained. The acetic acid was used to suppress the transesterification side reaction caused by the methanol solvent. After the second mixed solution is subjected to vacuum distillation, an alkaline regulator is added to adjust the pH value of the second mixed solution, and the crude neotame product is precipitated. The crude neotame product is then purified to obtain neotame.
2. The production method for improving neotame quality as described in claim 1, characterized in that, The Ni content in the Raney nickel catalyst is ≥90%.
3. The production method for improving neotame quality as described in claim 1, characterized in that, The molar ratio of the aspartame to the 3,3-dimethylbutyraldehyde is from 1:0.95 to 1:1.
05.
4. The production method for improving neotame quality as described in claim 1, characterized in that, The molar ratio of the Raney nickel catalyst to the 3,3-dimethylbutyraldehyde is from 0.05:1 to 0.25:
1.
5. The production method for improving neotame quality as described in claim 1, characterized in that, The alkalinity regulator is sodium bicarbonate, and the molar ratio of sodium bicarbonate to acetic acid is 1:0.8 to 1:0.
9.
6. The production method for improving neotame quality as described in claim 5, characterized in that, The second mixed solution is subjected to vacuum distillation, and then an alkaline regulator is added to adjust the pH of the second mixed solution to 7.5 to 8.5 in order to precipitate the crude neotame product.
7. The production method for improving neotame quality as described in claim 1, characterized in that, The hydrogenation pressure for the hydrogenation reduction reaction, in which hydrogen gas is introduced into the first mixed solution after the condensation reaction, is 0.8 MPa to 1.0 MPa, and the hydrogenation temperature is 30℃ to 45℃.
8. The production method for improving neotame quality as described in claim 1, characterized in that, The step of precipitating neotame crude product by adding an alkaline regulator to adjust the pH value of the second mixed solution after vacuum distillation includes: The second mixed solution was subjected to vacuum distillation to recover methanol. After distillation, the alkaline regulator and soft water were added, and the mixture was stirred, cooled, and centrifuged to obtain neotamecin product. The neotame crude product was added to anhydrous ethanol to remove odor, then frozen to crystallize, cooled, and centrifuged to obtain the neotame crude product.
9. The production method for improving neotame quality as described in claim 1, characterized in that, The preparation of neotame from the crude neotame product involves: adding the crude neotame product, activated carbon, and soft water to ethanol, stirring until homogeneous, heating for purification, filtering, cooling, and centrifuging to obtain the neotame.
10. The production method for improving neotame quality as described in claim 9, characterized in that, The amount of activated carbon added is 0.5%-0.8% of the amount of neotame crude product added.