Synthesis method and application of magnesium L-threonate

Abstract

The invention discloses a synthesis method of magnesium L-threonate. The synthesis method comprises the following steps: S1, preparing food-grade calcium L-threonate into an aqueous solution; s2, oxalic acid is added into the aqueous solution according to the molar ratio of 1: 1, and ultrasonic treatment is conducted for 30 min or above; s3, performing water bath treatment on the reaction mixed solution in a water bath at 0-4 DEG C, and then filtering to remove precipitates to obtain an L-threonic acid solution; s4, adding excessive magnesium oxide micro powder into the L-threonic acid solution, reacting, naturally cooling to room temperature, and filtering to remove precipitate to obtain an L-magnesium threonate solution; and S5, adding absolute ethyl alcohol into the magnesium L-threonate solution, then filtering to obtain a precipitate, washing the precipitate with absolute ethyl alcohol, and carrying out vacuum drying until the weight is constant, thereby obtaining the magnesium L-threonate. The invention further discloses the synthesis method and application in the pharmaceutical field. The synthesis efficiency is relatively high, the overall yield is also high, and it can be ensured that the purity of the synthesized magnesium L-threonate is high.

Description

Technical Field

[0001] The present application relates to the field of biomedicine technology, and in particular to a method for synthesizing magnesium L-threonate and its application. Background Art

[0002] As a carrier of metal ions, L-threonic acid can make metal ions easily bind to amino acids or proteins and be absorbed and utilized by humans or animals. Metal compounds of L-threonic acid have good application prospects as trace element supplements for the human body. For example, the commonly used calcium L-threonate has been widely used as a calcium supplement and has a good calcium supplement effect on the human body. Magnesium L-threonate is a magnesium compound of L-threonic acid and is a magnesium supplement developed by scientists in recent years. The compound was approved by the US FDA in 2014 and used in clinical practice as a potent magnesium supplement.

[0003] Whether L-threonate magnesium is used as a magnesium supplement for clinical drugs or as a food additive for food processing, its purity has extremely strict requirements. At present, the prior art method for synthesizing L-threonate magnesium mostly uses vitamin C as a raw material, hydrogen peroxide as an oxidant, and magnesium salts or magnesium oxide as a salt-forming agent, and synthesizes under aqueous reaction conditions. For example, the publication number is CN115894216A, and the invention name is a Chinese invention patent for a method for preparing L-threonate magnesium; for another example, the publication number is CN117004659A, and the invention name is a Chinese invention patent for a method for preparing a L-threonate magnesium powder, all of which use the above-mentioned synthesis method.

[0004] The above-mentioned prior art synthesis method can synthesize L-threonate magnesium with extremely high purity, and the magnesium content can be stabilized at more than 8%, and the quality is good. However, the above-mentioned prior art synthesis method has a long synthesis process cycle and low synthesis efficiency; in addition, the overall yield is generally around 75%, and the overall yield is relatively low. Summary of the invention

[0005] In order to solve at least one of the above technical problems, a synthesis method with relatively high synthesis efficiency and overall high yield, which can also ensure the high purity of the synthesized L-magnesium threonate is developed. The present application provides a synthesis method and application of L-magnesium threonate.

[0006] On the one hand, the present application provides a method for synthesizing magnesium L-threonate, comprising the following steps: S1. Dissolve food-grade L-calcium threonate in pure water to prepare a 0.04-0.05 mol / L solution; S2. Accurately add oxalic acid to the solution prepared in step S1 at a molar ratio of calcium L-threonate to oxalic acid of 1:1, and perform ultrasonic treatment for more than 30 minutes to obtain a reaction mixture; S3, placing the reaction mixture obtained in step S2 in a water bath at 0-4°C for more than 30 minutes, and then filtering to remove the precipitate, washing the precipitate with pure water whose total water volume does not exceed 1 / 10 of the volume of the solution prepared in step S1, combining the filtrate obtained by filtration with the washing water to obtain an L-threonic acid solution; S4, accurately adding magnesium oxide powder to the L-threonic acid solution obtained in step S3 according to a feeding ratio of 1:1.1-1.5 of calcium L-threonate to magnesium oxide powder, ultrasonically treating at a temperature of 80-85°C for more than 60 minutes, and then naturally cooling to room temperature under the condition of ultrasonic treatment, and then filtering to remove the precipitate, washing the precipitate with pure water, combining the filtrate obtained by filtration with the washing water to obtain an L-threose magnesium solution; S5. To the L-threose magnesium solution obtained in step S4, add anhydrous ethanol whose volume is 40-80% of the volume of the L-threose magnesium solution, stir for more than 15 minutes, and then filter out the precipitate, wash the precipitate with anhydrous ethanol, and vacuum dry it to constant weight to obtain L-threonate magnesium.

[0007] Optionally, in step S1, the purity of food-grade calcium L-threonate is above 99.5%.

[0008] Optionally, in step S2, the temperature of the ultrasonic treatment is controlled at 42-48°C.

[0009] Optionally, in step S2, the ultrasonic power of the ultrasonic treatment is 220-260 W, and the ultrasonic treatment time is 45-60 min.

[0010] Optionally, in step S3, the precipitate is washed more than three times with pure water having a total water volume not exceeding 1 / 10 of the volume of the solution prepared in step S1.

[0011] Optionally, in step S3, the obtained precipitate is filtered out and dried to constant weight to obtain the calcium oxalate byproduct for reuse.

[0012] Optionally, in step S4, the precipitate is washed more than three times with pure water having a total water volume not exceeding 1 / 10 of the volume of the L-threonic acid solution obtained in step S3.

[0013] Optionally, in step S4, the obtained precipitate is filtered out and dried to constant weight to obtain magnesium oxide for reuse.

[0014] Optionally, in step S4, the ultrasonic power of the ultrasonic treatment is 220-260 W, and the ultrasonic treatment time is 75-90 min.

[0015] On the other hand, the present application provides the use of L-threonate synthesized by the above-mentioned L-threonate synthesis method in the field of preparation of drugs for treating cognitive impairment diseases.

[0016] In summary, the present invention includes at least one of the following beneficial technical effects: 1. This application uses high-purity L-threonate calcium, a compound that has been maturely applied in the market, as a raw material, first displaces it with oxalic acid to obtain an L-threonate solution; then uses excess magnesium oxide as a salt-forming agent to obtain L-threonate magnesium; the overall yield of the synthesis method is extremely high, which can reach more than 94%, far exceeding the synthesis method of the prior art.

[0017] 2. The synthesis method of the present application carries out precise control of the reaction conditions in the oxalic acid replacement step, which can ensure that the reaction is complete and all calcium oxalate is precipitated and removed; in addition, in the step of preparing L-magnesium threonate using excess magnesium oxide as a salt-forming agent, the reaction conditions are also precisely controlled, which can greatly ensure the purity of the prepared L-magnesium threonate; the purity of the magnesium L-threonate prepared by the synthesis method of the present application is not lower than that of the magnesium L-threonate prepared by the prior art.

[0018] 3. The synthesis method of the present application can greatly shorten the synthesis time by designing the reaction conditions. The total time of the entire synthesis method can be controlled within 5 hours, which is highly efficient and suitable for large-scale production. In addition, in the synthesis method of the present application, the intermediate by-product calcium oxalate and the filtered residual magnesium oxide have high purity and can be reused, which can greatly reduce costs and cause minimal pollution to the environment.

[0019] 4. The L-magnesium threonate prepared by the synthesis method of the present application has extremely high purity and fully meets the standards for pharmaceutical use. With the support of existing literature, the L-magnesium threonate prepared by the present application can be widely used in the preparation of drugs for the treatment of cognitive impairment diseases. DETAILED DESCRIPTION

[0020] The following is a description of the implementation of the present invention by specific embodiments. People familiar with the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] The present application provides a method for synthesizing magnesium L-threonate, comprising the following steps: S1. Dissolve food-grade L-calcium threonate in pure water to prepare a 0.04-0.05 mol / L solution; S2. Accurately add oxalic acid to the solution prepared in step S1 at a molar ratio of calcium L-threonate to oxalic acid of 1:1, and perform ultrasonic treatment for more than 30 minutes to obtain a reaction mixture; S3, placing the reaction mixture obtained in step S2 in a water bath at 0-4°C for more than 30 minutes, and then filtering to remove the precipitate, washing the precipitate with pure water whose total water volume does not exceed 1 / 10 of the volume of the solution prepared in step S1, combining the filtrate obtained by filtration with the washing water to obtain an L-threonic acid solution; S4, accurately adding magnesium oxide powder to the L-threonic acid solution obtained in step S3 according to a feeding ratio of 1:1.1-1.5 of calcium L-threonate to magnesium oxide powder, ultrasonically treating at a temperature of 80-85°C for more than 60 minutes, and then naturally cooling to room temperature under the condition of ultrasonic treatment, and then filtering to remove the precipitate, washing the precipitate with pure water, combining the filtrate obtained by filtration with the washing water to obtain an L-threose magnesium solution; S5. To the L-threose magnesium solution obtained in step S4, add anhydrous ethanol whose volume is 40-80% of the volume of the L-threose magnesium solution, stir for more than 15 minutes, and then filter out the precipitate, wash the precipitate with anhydrous ethanol, and vacuum dry it to constant weight to obtain L-threonate magnesium.

[0022] Prior to this application, the existing technology for industrialized and large-scale production of L-threonate magnesium mainly used vitamin C as raw material, hydrogen peroxide oxidation, and then a salt-forming agent to form a salt. The main reason for adopting the above process is that L-threonate magnesium has current mandatory standards and strict requirements on its purity, whether it is used in the food field or in the health care product field.

[0023] In the literature disclosed in the prior art, in addition to the above-mentioned synthesis process of the prior art, there is also a second synthesis process under laboratory conditions. That is, using ion replacement, using calcium L-threonate as a raw material, using an ion exchange resin or an ion exchange reagent, L-threonate calcium is converted into L-threonic acid; then, a magnesium salt-forming agent is used to react with L-threonic acid to prepare magnesium L-threonate.

[0024] The reason why the prior art has abandoned the second process mentioned above is mainly based on the following factors. First, the cost of using ion exchange resins for large-scale production is too high; and when using ion exchange reagents such as oxalic acid, the obtained L-threonate magnesium will be mixed with magnesium oxalate impurities, and the purity is difficult to meet the requirements. The preparation of L-threonate magnesium in the laboratory is mainly used for research, and there is no excessive requirement for purity, so the synthesis process can be selected at will. In addition, the use of ion exchange process to prepare L-threonate magnesium will produce a large amount of solid waste and wastewater, which will pollute the environment.

[0025] Based on the consideration of overall yield, the present application has made substantial improvements to the synthesis process of preparing L-magnesium threonate by ion exchange under laboratory conditions, effectively solving the above-mentioned problems.

[0026] The following are examples of the present application: The sources of the main raw materials used in the examples of this application are as follows: Calcium L-threonate, food grade, two types (purity 98.5% and purity 99.5%), were purchased from Nanjing Tongying Biotechnology Co., Ltd.; oxalic acid, purity not less than 99.6%, was purchased from Suzhou Aorong Chemical Technology Co., Ltd.; magnesium oxide powder, purity 99.9%, particle size 50~200μm, was purchased from Weifang Lihe Powder Technology Co., Ltd.

[0027] Embodiment 1 The method for synthesizing magnesium L-threonate of this embodiment comprises the following steps: S1. Accurately weigh 115 g of food-grade L-calcium threonate with a purity of 98.5%, dissolve it in pure water to prepare a 0.05 mol / L solution; S2. Accurately add oxalic acid to the solution prepared in step S1 at a molar ratio of calcium L-threonate to oxalic acid of 1:1, and perform ultrasonic treatment for 30 min at room temperature and an ultrasonic power of 300 W to obtain a reaction mixture; S3, placing the reaction mixture obtained in step S2 in an ice water bath at 0-4°C for 30 min, filtering to remove the precipitate, washing the precipitate with 800 mL of pure water for 3 times, combining the filtrate obtained by filtration with the washing water to obtain an L-threonic acid solution; S4, to the L-threonic acid solution obtained in step S3, according to the molar ratio of L-threonate calcium to magnesium oxide powder of 1:1.1, accurately add magnesium oxide powder, control the reaction temperature at 80-85 ° C, 300 W ultrasonic power conditions, ultrasonic treatment for 60 minutes, and then continue the ultrasonic treatment condition, naturally cool to room temperature; filter the cooled mixed solution to remove the precipitate, wash the precipitate 3 times with 200 mL of pure water, and combine the filtrate obtained by filtration with the washing water to obtain L-threose magnesium solution; S5. Add 4.5 L of anhydrous ethanol to the L-threonate magnesium solution obtained in step S4, stir for 15 min, and then filter out the precipitate. After the precipitate is repeatedly washed with anhydrous ethanol for 3 times, it is vacuum dried to constant weight to obtain L-threonate magnesium.

[0028] Embodiment 2 The difference between this embodiment and the first embodiment is that in step S1, a 0.04 mol / L solution is prepared.

[0029] Embodiment 3 The difference between this embodiment and the first embodiment is that in step S2, the temperature of the ultrasonic treatment is controlled at 42-48°C.

[0030] Embodiment 4 The difference between this embodiment and the third embodiment is that in step S2, the ultrasonic power of the ultrasonic treatment is 220 W, and the ultrasonic treatment time is 60 min.

[0031] Embodiment 5 The difference between this embodiment and the third embodiment is that in step S2, the ultrasonic power of the ultrasonic treatment is 260 W, and the ultrasonic treatment time is 45 min.

[0032] Embodiment 6 The difference between this embodiment and the fifth embodiment is that in step S4, magnesium oxide powder is accurately added according to a feeding ratio of calcium L-threonate to magnesium oxide powder of 1:1.5 in molar ratio.

[0033] Embodiment 7 The difference between this embodiment and the fifth embodiment is that in step S4, magnesium oxide powder is accurately added according to a feeding ratio of calcium L-threonate to magnesium oxide powder of 1:1.3 in molar ratio.

[0034] Embodiment 8 The difference between this embodiment and the seventh embodiment is that in step S4, the ultrasonic power of the ultrasonic treatment is 220 W, and the ultrasonic treatment time is 90 min.

[0035] Embodiment 9 The difference between this embodiment and the eighth embodiment is that in step S4, the ultrasonic power of the ultrasonic treatment is 260 W, and the ultrasonic treatment time is 75 min.

[0036] Embodiment 10 The difference between this embodiment and Embodiment 9 is that in step S1, food-grade L-calcium threonate with a purity of 99.5% is used.

[0037] Comparative Example 1 Example 1 of the Chinese invention patent with publication number CN117004659A and invention name "A method for preparing magnesium L-threonate powder" is used as comparative example 1 of the present application.

[0038] Comparative Example 2 The difference between this comparative example and Example 10 is that in step S2, the ultrasonic treatment is changed to a stirring reaction at a rotation speed of 800 rpm for 8 hours.

[0039] Comparative Example 3 The difference between this comparative example and Example 10 is that in step S3, no water bath treatment step is adopted, and the precipitate is directly filtered out.

[0040] Detection: Magnesium L-threonate was prepared using the preparation methods of Examples 1 to 10 and Comparative Examples 1 to 3 of the present application. The reaction steps were detected by HPLC to calculate the total yield of the reaction; the purity of the prepared magnesium L-threonate was detected by HPLC.

[0041] The test results are shown in Table 1 below.

[0042] Table 1 Test results of examples and comparative examples It can be seen from the data in Table 1 that the purity of L-magnesium threonate obtained by the preparation methods of Examples 1 to 10 of the present application is at the same level as that of the preparation method of Comparative Example 1, and is slightly improved; and the preparation method of the present application has a yield of more than 92%, which is far higher than the yield of 73.6% of Comparative Example 1, and the yield has been greatly improved.

[0043] From the data in Table 1, it can be seen from the data comparison of Example 10 and Comparative Examples 2 to 3 that in the step of replacing calcium L-threonate with L-threonic acid in the present application, the ultrasonic treatment and the subsequent ice-water bath step have a greater impact on the yield and purity of the product. If ultrasonic treatment is not used, the oxalic acid replacement cannot react completely, which will lead to the presence of magnesium oxalate impurities in the final product, affecting the purity; and without an ice-water bath, calcium oxalate cannot be precipitated and removed as much as possible, which will also affect the purity of the final product.

[0044] From the data in Table 1, it can be seen from the data comparison of Example 1 to Example 10 that the preparation method of the present application optimizes the reaction parameters of step S2 and step S4, which has a promoting effect on the overall yield and can further improve the purity of the obtained L-threonate magnesium. In step S4, the reaction under ultrasonic conditions can effectively improve the salt formation rate and greatly improve the yield. In the step S4 salt formation reaction, the applicant uses the traditional stirring reaction method to conduct experiments, which is not only very time-consuming, but also the yield will drop by at least 1.5%.

[0045] In addition, the steps S2 and S4 of the present application adopt the reaction under ultrasonic conditions, which can not only ensure the complete reaction, guarantee the purity and high yield of the product, but also greatly shorten the synthesis time, and the entire synthesis process can be completed within a few hours.

[0046] At present, the existing technical literature has relevant disclosures about the medical effects of magnesium L-threonate. Journals such as "Chinese Journal of Pain Medicine", "Chinese Journal of Behavioral Medicine and Brain Science" and "Huaxia Medicine" all have animal experimental studies on the ability of magnesium L-threonate to repair brain white matter damage and / or improve cognitive impairment. Foreign countries have also published literature on the clinical verification of the medical effects of magnesium L-threonate in improving human memory function and improving human cognitive impairment. It can be seen that magnesium L-threonate has great application prospects in the preparation of drugs for the treatment of cognitive impairment diseases (such as Alzheimer's disease, etc.).

[0047] The L-magnesium threonate obtained by the synthesis method of the present application has extremely high purity, fully meets the application requirements in the pharmaceutical field, and can be fully applied to the above-mentioned fields.

[0048] Those skilled in the art will readily appreciate other embodiments of the present disclosure after considering the specification and practicing the disclosure disclosed herein. The present disclosure is intended to cover any variations, uses or adaptations of the present disclosure that follow the general principles of the present disclosure and include common knowledge or customary technical means in the art that are not disclosed in the present disclosure.

Claims

1. A method for synthesizing magnesium L-threonate, characterized in that: The following steps are involved: S1. Dissolve food-grade L-calcium threonate in pure water to prepare a 0.04-0.05 mol / L solution; S2. Accurately add oxalic acid to the solution prepared in step S1 at a molar ratio of calcium L-threonate to oxalic acid of 1:1, and perform ultrasonic treatment for more than 30 minutes to obtain a reaction mixture; S3, placing the reaction mixture obtained in step S2 in a water bath at 0-4°C for more than 30 minutes, and then filtering to remove the precipitate, washing the precipitate with pure water whose total water volume does not exceed 1 / 10 of the volume of the solution prepared in step S1, combining the filtrate obtained by filtration with the washing water to obtain an L-threonic acid solution; S4, accurately adding magnesium oxide powder to the L-threonic acid solution obtained in step S3 according to a feeding ratio of 1:1.1-1.5 of calcium L-threonate to magnesium oxide powder, ultrasonically treating at a temperature of 80-85°C for more than 60 minutes, and then naturally cooling to room temperature under the condition of ultrasonic treatment, and then filtering to remove the precipitate, washing the precipitate with pure water, combining the filtrate obtained by filtration with the washing water to obtain an L-threose magnesium solution; S5. To the L-threose magnesium solution obtained in step S4, add anhydrous ethanol whose volume is 40-80% of the volume of the L-threose magnesium solution, stir for more than 15 minutes, and then filter out the precipitate, wash the precipitate with anhydrous ethanol, and vacuum dry it to constant weight to obtain L-threonate magnesium.

2. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S1, the purity of food-grade calcium L-threonate is above 99.5%.

3. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S2, the temperature of the ultrasonic treatment is controlled at 42-48°C.

4. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S2, the ultrasonic power of the ultrasonic treatment is 220-260 W, and the ultrasonic treatment time is 45-60 min.

5. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S3, the precipitate is washed more than three times with pure water having a total water volume not exceeding 1 / 10 of the volume of the solution prepared in step S1.

6. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S3, the obtained precipitate is filtered out and dried to constant weight to obtain the calcium oxalate byproduct for reuse.

7. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S4, the precipitate is washed more than three times with pure water having a total water volume not exceeding 1 / 10 of the volume of the L-threonic acid solution obtained in step S3.

8. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S4, the obtained precipitate is filtered out and dried to constant weight to obtain magnesium oxide for reuse.

9. The method for synthesizing magnesium L-threonate according to claim 1, characterized in that: In step S4, the ultrasonic power of the ultrasonic treatment is 220-260 W, and the ultrasonic treatment time is 75-90 min.

10. Use of magnesium L-threonate synthesized by the method for synthesizing magnesium L-threonate according to any one of claims 1 to 9 in the preparation of drugs for treating cognitive impairment diseases.

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