A preparation process of high-purity lactulose

Abstract

The present invention relates to a preparation process of high-purity lactulose. The boric acid group contained in the boric acid ionic liquid of the present invention is selectively combined with lactulose generated by isomerization reaction, and lactulose is further extracted into the ionic liquid, thereby eliminating the product inhibition, so that the isomerization reaction proceeds in the direction of generating lactulose, thereby greatly improving the lactulose yield. The lactulose extracted into the ionic liquid exists in the form of [lactulose-boric acid complex]. By adding an acidic aqueous solution, the [lactulose-boric acid complex] is decomposed into lactulose and a boric acid ionic liquid, and the dissociated lactulose enters the acidic aqueous solution to obtain a high-purity lactulose solution, and the dissociated boric acid ionic liquid can be repeatedly recycled for a new batch of isomerization reactions. The preparation process of the present invention has mild reaction conditions, recyclable reaction catalysts, energy saving and environmental protection, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of functional sugar preparation, and in particular to a preparation process of high-purity lactulose. Background Art

[0002] Lactulose is a non-digestible oligosaccharide with unique functional properties. It was first discovered and named by Montgomery et al. in 1929. Lactulose is a potent prebiotic with unique prebiotic effects. It can inhibit the growth of a variety of pathogens and promote the proliferation of beneficial intestinal bacteria (including lactic acid bacteria and bifidobacteria). It has a wide range of applications in the fields of health food and clinical medicine. The preparation of lactulose by lactose isomerization is a typical aldose-ketose isomerization reaction, which mainly includes two pathways: enzymatic isomerization and chemical isomerization.

[0003] The bio-enzymatic isomerization of lactose to produce lactulose is highly favored due to its mild catalytic conditions, less environmental pollution and higher product safety. The enzymes reported for the preparation of lactulose can be divided into two categories, namely traditional glycosyl hydrolases and cellobiose isomerases. The glycosyl hydrolases used for the preparation of lactulose mainly include β -Glucosidase and β -galactosidase. β -galactosidase is already a commonly used enzyme preparation. Large enzyme preparation companies all have relevant β -galactosidase preparation; however, its disadvantage is that the reaction process not only requires a high concentration of fructose as a galactosyl acceptor, but also the final lactulose yield is very low. Cellobiose isomerase was first described by Tyler and Leatherwood in 1967. Ruminococcus albus ( Ra CE) found that Ra The epimeric activity of CE can catalyze the conversion of the glucosyl group of cellobiose into mannosyl group.

[0004] Although the bio-enzymatic method for preparing lactulose has many advantages, there is still a lack of an efficient and industrially applicable enzyme preparation for lactulose preparation. Therefore, the current commercial preparation of lactulose is still mainly based on chemical methods. Depending on the catalyst used, the chemical isomerization method for preparing lactulose can be divided into: alkaline catalyst method and complex catalyst method.

[0005] The alkaline catalysts used for the preparation of lactulose by chemical isomerization include: homogeneous alkaline catalysts and natural alkaline catalysts (including natural sepiolite, eggshell, shell and limestone, etc.). The use of alkaline catalysts to catalyze the preparation of lactulose from lactose has a significant thermodynamic equilibrium inhibition effect. In addition, the generated lactulose will also produce a strong product inhibition effect, which will reversely inhibit the formation of lactulose. At the same time, under high temperature and strong alkaline environment, the generated lactulose will be further degraded. In recent years, high-pressure assistance, high-intensity ultrasound assistance and microwave assistance have been used to assist the isomerization of lactulose with alkaline catalysts. The above measures have certain advantages in shortening the reaction time and reducing the reaction temperature, but have almost no effect on the yield of lactulose. The yield of lactulose prepared by isomerization using alkaline catalysts is very limited (<30%) and the output is low. In addition, the final product, in addition to low-concentration lactulose and residual lactose, also contains a large amount of by-products such as sugar acids, monosaccharides (mainly galactose) and pigments. In addition, the presence of homogeneous alkaline catalysts makes the purification of high-purity lactulose very difficult, which seriously restricts the further development of chemical isomerization in the industrial preparation of lactulose.

[0006] The application of complex catalysts helps to overcome the unfavorable thermodynamic equilibrium and product inhibition in the aldose-ketose isomerization reaction and improve the yield of lactulose. In the lactose-lactulose isomerization system, the most commonly used complex catalysts are boric acid, sodium aluminate and organic germanium (Ge-132) reported in recent years. Due to the stronger affinity of the complex catalyst with lactulose, in a strong alkaline environment, the complex catalyst will preferentially complex with the lactulose generated by isomerization to generate anionic complexes such as lactulose-boric acid, lactulose-aluminate and lactulose-organic germanium, which reduces the inhibitory effect of the product lactulose and promotes the isomerization reaction to continue in the positive direction of lactulose. The formed lactulose complex can also prevent the degradation of lactulose in a strong alkaline environment. The lactulose complex can be dissociated by acidification to release free lactulose and the complex catalyst. Complex catalysts can greatly increase the efficiency of isomerization reactions to 70-87%, and the isomerization temperature is low (60°C~70°C), the required reaction time is shorter, and the lactulose yield is higher. However, the disadvantages of complex catalysts are also very obvious, that is, how to efficiently separate the complex catalyst from the isomerized syrup. Taking the removal of boric acid as an example, expensive professional deboronization resins are required. However, from another perspective, if the complex catalyst can be solidified by appropriate technical means, it will help to exert its auxiliary isomerization performance. At the same time, the solidified complex catalyst is easy to separate, avoiding complex and expensive subsequent processing steps.

[0007] CN118496559A discloses a low pKa type phenylboronic acid carrier, which can efficiently separate and purify ketose (tagatose, lactulose, etc.) under neutral conditions, and the low pKa type phenylboronic acid carrier can be recycled and regenerated. CN111454305A discloses the specific affinity adsorption effect between the phenylboronic acid functional group carried by the phenylboronic acid polymer carrier and the lactulose containing the ortho-cis hydroxyl structure, and realizes the directional selective adsorption of lactulose in the lactose isomerization system, and promotes the isomerization reaction to proceed in the direction of generating lactulose, which can greatly improve the conversion rate of the target product, and the final lactulose yield can reach more than 65%, and the purity of the desorption liquid can be as high as more than 95%. The above method needs to load phenylboronic acid, which increases the preparation cost of the catalyst. CN111138501A adopts a two-phase system, selectively combines lactulose with phenylboronic acid compounds and extracts it into an organic phase, promotes the isomerization reaction of lactose to produce lactulose, and improves the yield of lactulose; and the lactulose extracted into the organic phase can be released into an acidic aqueous solution by reverse desorption to obtain a high-purity lactulose solution, achieving efficient catalysis and separation and purification to prepare high-purity lactulose. This method requires the use of a large amount of organic solvents, which increases costs and wastewater treatment costs.

[0008] In summary, it can be seen that the existing technology for the chemical preparation of lactulose is still insufficient. Therefore, it is of great economic value to develop a preparation process for high-purity lactulose suitable for industrialization. Summary of the invention

[0009] In order to solve the above technical problems existing in the prior art, the present invention provides a preparation process of high-purity lactulose. The preparation process of the present invention has mild reaction conditions, the reaction catalyst can be recycled, energy-saving and environmentally friendly, and is more suitable for industrial production.

[0010] The present invention provides a process for preparing lactulose, comprising the following steps:

[0011] 1) In the presence of boric acid ionic liquid and alkali, the lactose aqueous solution undergoes an isomerization reaction to convert lactose into lactulose, and the generated lactulose enters the boric acid ionic liquid;

[0012] 2) cooling the reaction solution of step 1) to room temperature, allowing it to stand, and separating the boric acid ionic liquid phase containing lactulose;

[0013] 3) adding the boric acid ionic liquid phase into the acidic aqueous solution for desorption, so that the lactulose is released into the acidic aqueous solution, thereby obtaining a high-purity lactulose solution;

[0014] The boric acid ionic liquid is selected from:

[0015] Wherein: n is an integer selected from 0 to 3,

[0016] R is selected from C 3-6 of alkyl.

[0017] Preferably, the boric acid ionic liquid in step 1) is selected from any one or more of AC shown below:

[0018] .

[0019] Preferably, the base in step 1) is selected from one or more combinations of sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate or calcium hydroxide;

[0020] Preferably, the amount of base added in step 1) is such that the pH of the lactose aqueous solution is > 7.5, more preferably 8.5-11.5;

[0021] Preferably, the concentration of lactose in the lactose aqueous solution in step 1) is 10 to 400 g / L, more preferably 100 to 300 g / L;

[0022] Preferably, the reaction temperature of step 1) is 30-80°C, more preferably 50-70°C.

[0023] Preferably, the reaction time of step 1) is 0.5-5 hours, more preferably 1-3 hours, most preferably 2-2.5 hours.

[0024] Preferably, in step 1), the mass ratio of lactose to boric acid ionic liquid is 1:2.0-5.0, more preferably 1:2.5-4.

[0025] Preferably, the reaction in step 1) is carried out under stirring, and the stirring speed is >150 r / min, preferably, the stirring speed is 200-800 r / min.

[0026] Preferably, the standing time in step 2) is 15 min to 2 h, more preferably 30 to 45 min;

[0027] Preferably, the acidic aqueous solution in step 3) is one or more combinations of hydrochloric acid, sulfuric acid, acetic acid, lactic acid or citric acid;

[0028] Preferably, the pH of the acidic aqueous solution in step 3) is less than 4.0; more preferably, the pH is 0 to 3;

[0029] Preferably, the volume ratio of the acidic aqueous solution to the boric acid ions in step 3) is 1 to 10: 1 ml / g.

[0030] Preferably, after step 3), the method further comprises neutralizing the aqueous solution containing lactulose with acid or alkali, concentrating or crystallizing the aqueous solution to obtain lactulose.

[0031] In recent years, the unique solvent properties of ionic liquids have made them widely used in the fields of synthesis and catalysis. People have designed various functionalized ionic liquids with specific catalytic properties by modifying the structure of ionic liquids. After a lot of work, the inventors found that in the presence of the boric acid ionic liquid of the present invention, the isomerization conversion of step 1) can be achieved under relatively mild conditions, and the yield and purity of the product are both high. The boric acid ionic liquid of the present invention is used as a catalyst, and the boric acid compound has a stronger affinity for lactulose. The boric acid group contained in the ionic liquid can selectively bind to the lactulose generated by the isomerization reaction, and further extract it into the ionic liquid, thereby eliminating the product inhibition, weakening the "thermodynamic limitation" in the aldose-ketose isomerization reaction, and making the isomerization reaction proceed in the direction of generating lactulose, thereby greatly improving the yield of lactulose. The lactulose extracted into the ionic liquid exists in the form of [lactulose-boric acid complex]. By adding an acidic aqueous solution, the [lactulose-boric acid complex] is decomposed into lactulose and a boric acid-based ionic liquid. The dissociated lactulose enters the acidic aqueous solution to obtain a high-purity lactulose solution, and the dissociated boric acid-based ionic liquid can be repeatedly recycled for a new batch of isomerization reactions. The use of ionic liquids in the production process of lactulose has not been reported in the literature and is the inventor's first invention.

[0032] Furthermore, the inventors found that in boric acid ionic liquids, when the carbon chain of the side chain is too short, due to the certain hydrophilicity of the boric acid itself, part of the ionic liquid will dissolve into water during the isomerization process of step 1) and the acidic decomposition process of step 3), thereby affecting the reaction efficiency, resulting in a decrease in yield and a decrease in product purity. However, when the carbon chain of the side chain is too long, during the reaction of step 1), the boric acid ionic liquid does not bind enough with water, and the phase separation effect is obvious, thereby affecting its extraction efficiency of lactulose, resulting in an incomplete isomerization reaction, reducing the reaction yield, and affecting the purity of the final product.

[0033] In addition, the boric acid ionic liquid of the present invention can be used as both a catalyst and an extraction reagent in step 1), and thus no organic solvent needs to be added, thereby saving costs. At the same time, since no solvent is required, the generation of wastewater during post-treatment is also reduced, thus meeting the requirements of green environmental protection.

[0034] Furthermore, the method of the present invention has simple post-processing, reduces the steps of separating boron ions in the prior art, simplifies the production process, and the obtained product has high purity, which is suitable for industrial production. DETAILED DESCRIPTION

[0035] The following examples are provided to illustrate the present invention in detail. The following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0036] Therefore, before describing the present invention in detail, it should be understood that the present invention is not limited to the system or process parameters of the specific examples which may vary of course. It should also be understood that the terms used herein are only for the purpose of describing a specific embodiment of the present invention, and are not intended to limit the scope of the present invention in any way. The examples used anywhere in this specification (including the examples of any terms discussed herein) are merely illustrative and in no way limit the scope and meaning of the present invention or any illustrative terms. Similarly, the present invention is not limited to the various embodiments given in this specification. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. In the event of a conflict, this document (including definitions) shall prevail.

[0037] The following boric acid ionic liquid was prepared according to the method of J. Chem. Eng. Data 2006, 51, 1274-1279:

[0038]

[0039] Example 1

[0040] Dissolve 200g of lactose in 1000mL of deionized water, stir evenly, and add NaOH to adjust the pH of the system to 10. Under stirring, add 600g of boric acid ionic liquid A. The above reaction mixture was heated to 60℃, reacted for 60min under high-speed stirring at 500r / min, and then the whole system was cooled to room temperature and allowed to stand for 30min. It was found that the reaction solution was layered, with the upper layer being the aqueous phase and the lower layer being the boric acid ionic liquid phase. The upper aqueous phase was separated, and 1000mL of hydrochloric acid aqueous solution (0.01mol / L, pH=2.0) was added to the lower boric acid ionic liquid phase, stirred at high speed at room temperature (speed of 500r / min), and reverse desorption was performed for 1h. After desorption was completed, lactulose dissociated into the upper acidic aqueous solution, and the acidic aqueous solution and the lower boric acid ionic liquid phase were centrifuged and collected. The boric acid ionic liquid A after reverse desorption was repeatedly used for the next batch of lactulose selective extraction.

[0041] The collected acidic aqueous solution was neutralized and concentrated to remove water, thereby obtaining 175 g of lactulose with a purity of 96.3% and a yield of 87.5%.

[0042] Example 2

[0043] The same method as in Example 1 was used, except that the same mass of boric acid ionic liquid B was used instead of boric acid ionic liquid A. 152 g of lactulose was obtained with a purity of 92.1% and a yield of 76.0%.

[0044] Example 3

[0045] The same method as in Example 1 was used, except that the same mass of boric acid ionic liquid C was used instead of boric acid ionic liquid A. 143 g of lactulose was obtained with a purity of 88.5% and a yield of 71.5%.

[0046] Example 4

[0047] Dissolve 150g of lactose in 1000mL of deionized water, stir evenly, and add KOH to adjust the pH of the system to 11. Under stirring, add 400g of boric acid ionic liquid A. The above reaction mixture was heated to 50℃, reacted for 100min under high-speed stirring at 500r / min, and then the whole system was cooled to room temperature and allowed to stand for 30min. It was found that the reaction solution was layered, with the upper layer being the aqueous phase and the lower layer being the boric acid ionic liquid phase. The upper aqueous phase was separated, and 800mL of hydrochloric acid aqueous solution (0.1mol / L, pH=1.0) was added to the lower boric acid ionic liquid phase, stirred at high speed at room temperature (speed of 500r / min), and reverse desorption was performed for 1h. After the desorption was completed, lactulose dissociated into the upper acidic aqueous solution, and the acidic aqueous solution and the lower boric acid ionic liquid phase were collected by centrifugation. The boric acid ionic liquid A after reverse desorption was repeatedly used for the next batch of lactulose selective extraction.

[0048] The collected acidic aqueous solution was neutralized and concentrated to remove water, thereby obtaining 133 g of lactulose with a purity of 94.8% and a yield of 88.6%.

[0049] Example 5

[0050] Dissolve 100g of lactose in 1000mL of deionized water, stir evenly, and add KOH to adjust the pH of the system to 10. Under stirring, add 400g of boric acid ionic liquid A. The above reaction mixture was heated to 70℃, reacted for 100min under high-speed stirring at 500r / min, and then the whole system was cooled to room temperature and allowed to stand for 30min. It was found that the reaction solution was layered, with the upper layer being the aqueous phase and the lower layer being the boric acid ionic liquid phase. The upper aqueous phase was separated, and 600mL of hydrochloric acid aqueous solution (0.01mol / L, pH=2.0) was added to the lower boric acid ionic liquid phase, stirred at high speed at room temperature (speed of 500r / min), and reverse desorption was performed for 1h. After desorption was completed, lactulose dissociated into the upper acidic aqueous solution, and the acidic aqueous solution and the lower boric acid ionic liquid phase were centrifuged and collected. The boric acid ionic liquid A after reverse desorption was repeatedly used for the next batch of lactulose selective extraction.

[0051] The collected acidic aqueous solution was neutralized and concentrated to remove water, thereby obtaining 91 g of lactulose with a purity of 95.2% and a yield of 91.0%.

Claims

1. A process for preparing lactulose, characterized in that The steps include: 1) In the presence of boric acid ionic liquid and alkali, the lactose aqueous solution undergoes an isomerization reaction to convert lactose into lactulose, and the generated lactulose enters the boric acid ionic liquid; 2) cooling the reaction solution of step 1) to room temperature, allowing it to stand, and separating the boric acid ionic liquid phase containing lactulose; 3) adding the boric acid ionic liquid phase into the acidic aqueous solution for desorption, so that the lactulose is released into the acidic aqueous solution, thereby obtaining a high-purity lactulose solution; The boric acid ionic liquid is selected from: 。 2. The preparation process according to claim 1, characterized in that: In step 1), the alkali is selected from one or more combinations of sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and calcium hydroxide. The amount of alkali added in step 1) is such that the pH of the lactose aqueous solution is greater than 7.

5.

3. The preparation process according to claim 1 or 2, characterized in that: The concentration of lactose in the lactose aqueous solution of step 1) is 10 to 400 g / L.

4. The preparation process according to claim 1 or 2, characterized in that: The reaction temperature of step 1) is 30-80°C.

5. The preparation process according to claim 1 or 2, characterized in that: In step 1), the mass ratio of lactose to boric acid ionic liquid is 1:2.0-5.

0.

6. The preparation process according to claim 1 or 2, characterized in that: Step 2) The standing time is 15min to 2h.

7. The preparation process according to claim 1 or 2, characterized in that: The acidic aqueous solution in step 3) is one or more combinations of hydrochloric acid, sulfuric acid, acetic acid, lactic acid or citric acid.

8. The preparation process according to claim 1 or 2, characterized in that: The pH of the acidic aqueous solution in step 3) is <4.

0.

9. The preparation process according to claim 1 or 2, characterized in that: After step 3), the method further includes neutralizing the aqueous solution containing lactulose with acid or alkali, concentrating or crystallizing the aqueous solution to obtain lactulose.

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