Preparation method of magnesium threonate

Abstract

The invention discloses a preparation method of magnesium threonate. The preparation method comprises the following steps: S1, preparing a stable glucose-magnesium six-membered ring compound; s2, concentrating the reaction liquid, crystallizing, and drying in vacuum to obtain a glucose-magnesium six-membered ring compound; s3, dissolving the compound in water, and adding Fe < 2 + > to adjust the pH value to 2.5-3.0; s4, the solution obtained in S3 is heated, H2O2 is dropwise added, Fe < 2 + > in the solution catalyzes H2O2 to generate hydroxyl radicals, the glucose-magnesium compound is selectively cracked, and magnesium threonate is generated; s5, adding Na2S2O3 to terminate the reaction, and filtering to remove Fe (OH) 3 precipitate; concentrating the filtrate under reduced pressure until the filtrate is sticky, standing at low temperature, and separating out a magnesium threonate crude product; according to the method, the glucose-magnesium six-membered ring compound is used as a raw material and is converted into magnesium threonate through Fenton reaction oxidative cracking, and the purified magnesium threonate is high in purity, low in Fe residue, mild in process condition and suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of preparing magnesium threonate, and in particular to a method for preparing magnesium threonate. Background Art

[0002] Magnesium threonate is a chelate formed by magnesium ions and threonic acid. It can increase the magnesium concentration in the brain through the blood-brain barrier and shows potential in improving synaptic plasticity and cognitive function.

[0003] Existing technologies, such as the invention patent applications with application numbers 2015104127839 and 2016104581370, mostly use vitamin C as raw material, hydrogen peroxide as oxidant, add magnesium hydroxide or remade magnesium carbonate to form salt, synthesize in pure water system, and use ethanol aqueous solution to crystallize at room temperature to obtain the product. The existing synthesis process mainly relies on the direct neutralization reaction of L-threonic acid and magnesium salt, which has the following defects: impurities such as oxalic acid are easily formed in the reaction, which requires multiple purifications. The EU assesses that the residual oxalic acid is as high as 1%; high-purity L-threonic acid relies on imports, and the raw material cost accounts for more than 60%; the process is complicated, and the pH (±0.2) and temperature (±2°C) need to be precisely controlled, otherwise the yield will drop to less than 70%; the traditional oxidant (such as chromate) causes excessive heavy metal residues, limiting the medicinal value. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing magnesium threonate. The method uses a glucose-magnesium six-membered ring complex as a raw material and converts it into magnesium threonate through oxidative cleavage by Fenton reaction. The purified magnesium threonate has high purity, low Fe residue, mild process conditions, and is suitable for large-scale production.

[0005] To solve this technical problem, the technical solution of the present invention is: a method for preparing magnesium threonate, comprising the following steps: S1, D-glucose and Mg in a weakly acidic buffer system with a pH of 5.0 to 5.5 2+ Coordination occurs to form a stable glucose-magnesium six-membered ring complex; S2, concentrating the reaction solution containing the glucose-magnesium six-membered ring complex obtained in step S1, crystallizing, and vacuum drying to obtain a white powder of the glucose-magnesium six-membered ring complex; S3, dissolving the white powder of the glucose-magnesium six-membered ring complex obtained in S2 in water, adding a soluble ferrous salt, and adjusting the pH to 2.5 to 3.0; S4, heat the solution obtained in S3, add H 2 O 2 , Fe in solution 2+ Catalytic H 2 O 2 The generated hydroxyl radical selectively cleaves the C2-C3 bond of the glucose-magnesium complex to generate magnesium threonate; HPLC monitoring of the disappearance of characteristic peaks of glucose; S5. Add Na to the S4 reaction system 2 S 2 O 3 Stop the reaction and filter to remove Fe(OH) 3 Precipitation; the filtrate is concentrated under reduced pressure to a viscous state, and allowed to stand at low temperature to precipitate the crude magnesium threonate.

[0006] Preferably, the preparation method for forming a stable glucose-magnesium six-membered ring complex in step S1 comprises the following steps: S11, dissolve soluble magnesium salt in deionized water, add acetic acid-sodium acetate buffer to adjust the pH of the system to 5.0 to 5.5, stir until the soluble magnesium salt is completely dissolved, and stabilize the magnesium with acetic acid-sodium acetate buffer. 2+ ; S12, D-glucose is added to the solution obtained in S11 to form a glucose-magnesium six-membered ring complex; S13, centrifuge the reaction solution, add NaOH to the supernatant until the pH is 10 without precipitation, indicating that Mg 2+ Fully coordinated.

[0007] The D-glucose of the present invention is reacted with Mg in a weakly acidic buffer system with a pH of 5.0 to 5.5. 2+ The present invention uses acetic acid-sodium acetate buffer to maintain the pH stability of the reaction solution, prevent the pH value from exceeding 6.0, and avoid Mg 2+ Under alkaline conditions, it precipitates as Mg(OH) 2 .

[0008] Preferably, D-glucose and Mg in step S12 2+ The reaction conditions for coordination are as follows: Stir at 50 to 60°C for 3 to 5 hours.

[0009] The invention controls the temperature of the coordination reaction to be 50-60°C, accelerates the coordination kinetics, avoids the carbonization of glucose caused by high temperature, and prevents the generation of 5-hydroxymethylfurfural when the reaction temperature exceeds 70°C.

[0010] Preferably, D-glucose and Mg in step S12 2+ The molar ratio of Mg is (1.2 to 1.9): 1. The present invention ensures that Mg is 2+ Complete coordination reduces side reactions caused by free magnesium ions, such as the formation of oxalic acid.

[0011] Preferably, in step S2, the reaction solution is concentrated to 1 / 4-1 / 3 of the original volume, and allowed to stand at 4° C. for 12 hours for crystallization; After centrifugation, the mixture was washed 4-6 times with 4°C precooled ethanol and vacuum dried to obtain a white powder of glucose-magnesium six-membered ring complex.

[0012] The present invention combines an acetic acid-sodium acetate buffer system with low-temperature ethanol purification, and the yield of the coordination complex is increased to more than 90%.

[0013] The present invention utilizes ethanol low-temperature crystallization, and the purification mechanism is that ethanol reduces the solubility of the complex, and low temperature inhibits the re-dissolution of impurities. The mechanism of purification by low-temperature ethanol crystallization in the present invention is a fine separation process based on solubility selectivity difference and dynamic crystallization control, and its core is to achieve differentiated precipitation and separation of the target and impurities through the synergistic effect of solvent-temperature. The present invention utilizes the dual-factor regulation of solvent-temperature: through the synergistic effect of ethanol addition (solvent composition change) and low temperature conditions, the solubility difference between the target and the impurity is expanded to achieve more efficient selective precipitation. Dynamic washing mechanism: utilizing the "low solubility-high flushing" characteristics of low-temperature ethanol, breaking through the limitations of traditional static crystallization and avoiding the formation of solid mixtures. In the present invention, the solubility of the coordination complex and impurities respond differently in the ethanol-water mixed system and low temperature conditions, and the coordination complex preferentially reaches the crystallization threshold. Impurities are mainly attached to the crystal surface by physical adsorption, rather than entering the interior of the crystal, and washing can effectively remove them. After crystallization, combined with multi-stage operations such as low-temperature washing and vacuum drying, impurity residues are systematically reduced. Through the above mechanism, the present invention achieves the step-by-step removal of impurities while ensuring a high yield of the composite, and the purity of the final product can reach more than 99.5%.

[0014] Preferably, the soluble ferrous salt added in step S3 accounts for 1% to 2% of the mass of the reaction solution, and sulfuric acid is used to adjust the pH of the reaction solution. The present invention controls the amount of the soluble ferrous salt to ensure that Fe 2+ The amount of catalytic H 2 O 2 Generate hydroxyl radicals (·OH), selectively cleave the C2-C3 bond of the glucose-magnesium complex to generate magnesium threonate; also avoid Fe 2+ Excessive dosage results in metal residue.

[0015] The process conditions for selective cracking in step S4 are preferably: The reaction temperature is 40°C to 50°C; Reaction time 4-6 hours; Add 30% H at a rate of 0.5 mL / min to 1.0 mL / min. 2 O 2 .

[0016] The present invention particularly requires that the reaction temperature be controlled not to exceed 50°C, and the temperature of the selective pyrolysis be adjusted to 40°C to 50°C to avoid excessively high reaction temperature. 2 O 2Ineffective decomposition, while ensuring the reaction efficiency, reduces the generation of by-products. 2 O 2 The dripping rate must match the temperature. Too fast a rate can easily lead to local overoxidation and affect product stability.

[0017] Preferably, the crude magnesium threonate obtained in S5 is dehydrated and recrystallized to purify the magnesium threonate. The specific purification process is as follows: The crude magnesium threonate obtained in S5 was dissolved in deionized water at 60°C to 80°C, and 5-10% activated carbon was added and stirred for 30 minutes; The mixture was filtered while hot, and the filtrate was slowly cooled to 25°C for crystallization, and then vacuum dried to obtain purified magnesium threonate.

[0018] Fe of the present invention 2+ Catalytic oxidative cracking combined with activated carbon decolorization process, activated carbon adsorbs pigments produced during oxidation, such as melanoidin, to improve the optical purity of the product; hot water recrystallization combined with temperature-dependent solubility differences removes trace Fe(OH) 3 And organic impurities make the purity of magnesium threonate exceed 95%.

[0019] Preferably, the solid-to-liquid ratio of the crude magnesium threonate dissolved in deionized water is 1:10.

[0020] By adopting the above technical solution, the beneficial effects of the present invention are: The present invention utilizes D-glucose and Mg 2+ In a weakly acidic buffer system with a pH of 5.0 to 5.5, coordination occurs to form a stable glucose-magnesium six-membered ring complex; the present invention utilizes coordination to capture Mg through D-glucose 2+ Then, the glucose-magnesium six-membered ring complex was used as the reactant to utilize the Fe 2+ Catalytic H 2 O 2 The generated hydroxyl radical selectively cleaves the C2-C3 bond of the glucose-magnesium complex to generate magnesium threonate, avoiding the problem of incomplete reaction of reactants during the reaction process. The purity of the purified product is higher than 95%; the residual Fe in magnesium threonate is less than 0.05ppm, which meets the standards for pharmaceutical excipients (USP-NF); When the reaction of the present invention is terminated, by adding Na 2 S 2 O 3 The residual oxidant is reduced to stop the cracking reaction. The pH of the solution increases due to the termination of the reaction. 3+ As the solution changes from weakly acidic to neutral conditions, a hydrolysis reaction occurs to generate water-insoluble iron hydroxide precipitate. The reaction formula is as follows: Fe 3+ +3H 2O→Fe(OH) 3 ↓+3H + ; Subsequent separation and purification can effectively reduce Fe residue; The present invention avoids the high temperature, strong acid / base or toxic oxidant (such as chromate) of the traditional oxidation process, reduces energy consumption and environmental pollution; the process conditions of the present invention are mild and suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The infrared spectrum of magnesium threonate obtained in Example 1; Figure 2 HPLC spectra of the products of Examples 1 to 8 of the present invention and the standard magnesium threonate, wherein S1 to S8 represent Examples 1 to 8 respectively. DETAILED DESCRIPTION

[0022] In order to further explain the technical solution of the present invention, the present invention is described in detail below through specific embodiments.

[0023] Example 1 This embodiment discloses a method for preparing magnesium threonate, comprising the following steps: S1, D-glucose and Mg in a weakly acidic buffer system at pH 5.2 2+ Coordination occurs to form a stable glucose-magnesium six-membered ring complex; The preparation method for forming a stable glucose-magnesium six-membered ring complex in step S1 comprises the following steps: S11, take 24.4gMgCl 2 6H 2 O (0.1 mol) was dissolved in 500 mL of deionized water, and 0.1 M acetic acid-sodium acetate buffer (pH 5.0) was added to adjust the system pH to 5.2. The mixture was stirred until completely dissolved. The acetic acid-sodium acetate buffer was used to stabilize the Mg 2+ ; S12, D-glucose is added to the solution obtained in S11 to form a glucose-magnesium six-membered ring complex; D-Glucose + Mg 2+ →[Mg(C 6 H 12 O 6 )] 2+ +2Cl - ; In step S12, D-glucose and Mg 2+ The reaction conditions for coordination are as follows: To the solution obtained in S11, 27.0 g of D-glucose (0.15 mol) was added and stirred at 55°C for 4 hours.

[0024] S13, endpoint detection: 5 mL of the reaction solution was centrifuged (8000 rpm, 10 min), and 0.1 M NaOH was added to the supernatant until pH 10. The solution was clear without precipitation, indicating that Mg 2+ Completely coordinated with glucose.

[0025] S2, concentrating the reaction solution containing the glucose-magnesium six-membered ring complex obtained in step S1, crystallizing, and vacuum drying to obtain a white powder of the glucose-magnesium six-membered ring complex; The reaction solution obtained in step S1 was concentrated to 150 mL under reduced pressure, transferred to a crystallization dish, and allowed to stand at 4°C for 12 hours for crystallization. The crystals were collected by centrifugation at 8000 rpm for 15 minutes, washed five times with 50 mL of 4°C precooled ethanol, and vacuum dried at 40°C for 8 hours to obtain 18.5 g of white powder of glucose-magnesium six-membered ring complex, with a yield of 82%.

[0026] S3, take 20.0g glucose-magnesium six-membered ring complex and dissolve it in 200mL water, add 0.3g FeSO 4 7H 2 O (1.5% w / w), diluted H 2 SO 4 The pH of the solution was adjusted to 2.8.

[0027] S4, heat the solution obtained in S3 to 45°C, and add 30% H 2 O 2 120mL, react for 5 hours. 2+ Catalytic H 2 O 2 The generated hydroxyl radical selectively cleaves the C2-C3 bond of the glucose-magnesium complex to generate magnesium threonate; End point determination: HPLC monitoring (C18 column, acetonitrile-water = 85:15, flow rate 1.0 mL / min, RI detector), the characteristic peak of glucose (8.2 min) disappeared.

[0028] S5, add 1.0gNa 2 S 2 O 3 Stop the reaction and filter to remove Fe(OH) 3 The filtrate was concentrated under reduced pressure to a viscous state and allowed to stand at 4°C for 24 hours to precipitate 14.3 g of crude magnesium threonate with a yield of 76%.

[0029] The crude magnesium threonate obtained in S5 was dissolved in 150 mL of 70°C hot water at a solid-liquid ratio of 1:10, and 1.2 g of activated carbon (8% w / w) was added and stirred for decolorization for 30 minutes. Filter while hot, and slowly cool the filtrate to 25°C at a rate of 0.5°C / min for crystallization. After filtration, vacuum dry at 60°C for 6 hours to obtain 12.8 g of white needle-shaped magnesium threonate with a final yield of 68%. The slow cooling rate in this embodiment is lower than 1°C / min, which can improve the regularity of the crystals and reduce the inclusion of impurities. High performance liquid chromatography (HPLC) analysis (area normalization method, C18 column, 0.1% H 3 PO 4 The magnesium threonate obtained in this embodiment has a purity of 99.6%, and the residual Fe in the obtained magnesium threonate detected by ICP-MS is 0.03 ppm; the magnesium threonate obtained in this embodiment is a white crystalline powder, which is easily soluble in water, and the pH value of the aqueous solution with a mass fraction of 1% is 6.5-7.0.

[0030] 1 mg of the magnesium threonate prepared in this example was mixed with 200 mg of KBr, ground and pressed into tablets for infrared spectroscopy (FT-IR) analysis. The obtained spectrum is as follows: Figure 1 By comparing the characteristic peaks of the sample prepared in Example 1 with those of magnesium threonate, the characteristic peaks of magnesium threonate can be found: Carboxylate peak: COO⁻ symmetric stretching vibration 1600cm -1 ; Hydroxyl (-OH) peak: OH stretching vibration (broad peak) 3400cm -1 ; Mg-O bond peak: Mg-O bond stretching vibration 500cm -1 .

[0031] Example 2 The difference between this embodiment and embodiment 1 is that in step S1, a pH buffer system is formed to adjust the solution to pH 5.5.

[0032] Example 3 The difference between this embodiment and embodiment 1 is that glucose and Mg 2+ The molar ratio is 1.9:1.

[0033] Example 4 The difference between this embodiment and embodiment 1 is that in step S2, the complex is washed 6 times with cold ethanol (4° C.) during the purification stage.

[0034] Example 5 The difference between this embodiment and embodiment 1 is that 30% H 2 O 2 20 mL, the temperature was controlled at 40 °C and stirred for 5 hours.

[0035] Example 6 The difference between this embodiment and embodiment 1 is that glucose and Mg 2+ The molar ratio is 1:1.

[0036] Example 7 The difference between this embodiment and embodiment 1 is that in step S2, the complex is washed twice with cold ethanol (4° C.) during purification.

[0037] Example 8 The difference between this embodiment and embodiment 1 is that 30% H 2 O 2 20mL, the selective pyrolysis temperature was controlled at 70°C and stirred for 5 hours.

[0038] High performance liquid chromatography (HPLC) was used to detect the purity and total yield of the magnesium threonate obtained in Examples 1 to 8. The specific data are shown in Table 1.

[0039] Table 1 Purity, yield, residual Fe and impurities of magnesium threonate obtained in Examples 1 to 8

[0040] No significant impurities were detected in Table 1, which means that the total impurity peaks were ≤0.4% by HPLC area normalization method. The reasons for the changes in the purity, yield, Fe residue and impurity conditions of the products obtained in Examples 1 to 8 are as follows: the pyrolysis reaction temperature in Example 5 was controlled at 40°C, which was lower than 45°C in Example 1, and H 2 O 2 The dripping rate is slower. The low temperature environment inhibits side reactions, such as excessive oxidation of glucose to produce oxalic acid or 5-hydroxymethylfurfural (HMF); at the same time, the low cracking reaction temperature is also conducive to improving selectivity, and the hydroxyl radical (·OH) more accurately cleaves the C2-C3 bond of the glucose-magnesium complex, reducing ineffective decomposition; in addition, the low cracking reaction temperature is conducive to reducing product degradation and avoiding the isomerization or decomposition of magnesium threonate caused by high temperature. In Example 6, due to the molar ratio of 1:1, glucose is insufficient, and the magnesium ions are not fully coordinated. The uncoordinated Mg 2+ The C2-C3 bond is not exposed in a directional manner, and ·OH randomly attacks other sites. ·OH attacks the C1-C2 bond to generate oxalic acid, and ·OH attacks the C3-C4 bond to generate HMF. In Example 7, only two washes resulted in Fe(OH) 3 In Example 8, the pyrolysis reaction temperature was 70°C, which caused the sugar dehydration side reaction and deepened the color, which was not conducive to obtaining the target product. The HPLC spectrum of magnesium threonate obtained in Examples 1 to 8 is as follows: Figure 2 shown.

[0041] Combined with the above data, it can be seen that the present invention is beneficial to D-glucose and Mg 2+In a weakly acidic buffer system with a pH of 5.0 to 5.5, coordination occurs to form a stable glucose-magnesium six-membered ring complex; the present invention utilizes coordination to capture Mg through D-glucose 2+ Then, the glucose-magnesium six-membered ring complex was used as the reactant to utilize the Fe 2+ Catalytic H 2 O 2 The generated hydroxyl radical selectively cleaves the C2-C3 bond of the glucose-magnesium complex to generate magnesium threonate, avoiding the problem of incomplete reaction of reactants during the reaction process. The purity of the purified product is higher than 95%; the residual Fe in magnesium threonate is less than 0.05ppm, which meets the standards for pharmaceutical excipients (USP-NF).

Claims

1. A method for preparing magnesium threonate, characterized in that: The following steps are involved: S1, D-glucose and Mg in a weakly acidic buffer system with a pH of 5.0 to 5.5 2+ Coordination occurs to form a stable glucose-magnesium six-membered ring complex; S2, concentrating the reaction solution containing the glucose-magnesium six-membered ring complex obtained in step S1, crystallizing, and vacuum drying to obtain a white powder of the glucose-magnesium six-membered ring complex; S3, dissolving the white powder of the glucose-magnesium six-membered ring complex obtained in S2 in water, adding a soluble ferrous salt, and adjusting the pH to 2.5 to 3.0; S4, heat the solution obtained in S3, add H2O2 dropwise, Fe 2+ Catalyze H2O2 to generate hydroxyl radicals, which selectively cleave the C2-C3 bond of the glucose-magnesium complex to generate magnesium threonate; HPLC monitoring of the disappearance of characteristic peaks of glucose; S5. Add Na2S2O3 to the reaction system of S4 to terminate the reaction, and filter to remove the Fe(OH)3 precipitate; the filtrate is concentrated under reduced pressure to a viscous state, and allowed to stand at low temperature to precipitate the crude magnesium threonate.

2. The preparation method according to claim 1, characterized in that: The preparation method for forming a stable glucose-magnesium six-membered ring complex in step S1 comprises the following steps: S11, dissolve the soluble magnesium salt in deionized water, add acetic acid-sodium acetate buffer to adjust the pH of the system to 5.0 to 5.5, stir until the soluble magnesium salt is completely dissolved, and stabilize the Mg with acetic acid-sodium acetate buffer. 2+ ; S12, D-glucose is added to the solution obtained in S11 to form a glucose-magnesium six-membered ring complex; S13, centrifuge the reaction solution, add NaOH to the supernatant until the pH is 10 without precipitation, indicating that Mg 2+ Fully coordinated.

3. The preparation method according to claim 2, characterized in that: In step S12, D-glucose and Mg 2+ The reaction conditions for coordination are as follows: Stir at 50 to 60°C for 3 to 5 hours.

4. The preparation method according to claim 2, characterized in that: In step S12, D-glucose and Mg 2+ The molar ratio is (1.2 to 1.9):

1.

5. The preparation method according to claim 1, characterized in that: In step S2, the reaction solution is concentrated to 1 / 4 to 1 / 3 of the original volume, and allowed to stand at 4° C. for 12 hours for crystallization; After centrifugation, the mixture was washed 4-6 times with 4°C precooled ethanol and vacuum dried to obtain a white powder of glucose-magnesium six-membered ring complex.

6. The preparation method according to claim 1, characterized in that: The soluble ferrous salt added in step S3 accounts for 1% to 2% of the mass of the reaction solution, and sulfuric acid is used to adjust the pH of the reaction solution.

7. The preparation method according to claim 1, characterized in that: The process conditions for selective cracking in step S4 are: The reaction temperature is 40°C to 50°C; The reaction time is 4 to 6 hours; H2O2 with a mass fraction of 30% was added dropwise at a rate of 0.5 mL / min to 1.0 mL / min.

8. The preparation method according to claim 1, characterized in that: The crude magnesium threonate obtained in S5 is dehydrated and recrystallized to purify the magnesium threonate. The specific purification process is as follows: The crude magnesium threonate obtained in S5 was dissolved in deionized water at 60°C to 80°C, and 5-10% activated carbon was added and stirred for decolorization; The mixture was filtered while hot, and the filtrate was slowly cooled to 25°C for crystallization, and then vacuum dried to obtain purified magnesium threonate.

9. The preparation method according to claim 8, characterized in that: The solid-liquid ratio of the crude magnesium threonate dissolved in deionized water is 1:10.

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