Preparation method of magnesium acetyltaurate

Abstract

The invention discloses a preparation method of magnesium acetyltaurate, which comprises the following steps: S1, preparing a taurine solution, and then adding acetic anhydride to prepare a reaction mixed solution; s2, adding N-acetyltransferase into the reaction mixed solution, carrying out enzymatic acetylation reaction, and then, carrying out vacuum concentration and crystallization, so as to obtain an acetyltaurine crude product; s3, cleaning the crude product with absolute ethyl alcohol, heating and drying to obtain a pure acetyltaurine product; s4, preparing an acetyltaurine solution, then adding magnesium methoxide, carrying out a heating reflux reaction, and then carrying out vacuum concentration crystallization to prepare a magnesium acetyltaurine crude product; and S5, washing the crude product with absolute methanol, heating and drying to obtain a pure product of magnesium acetyltaurate. The preparation cost is relatively low, and the prepared magnesium acetyltaurate is relatively high in purity, relatively low in impurity content and very suitable for the field of pharmacy.

Description

Technical Field

[0001] The present application relates to the field of biomedicine technology, and in particular to a method for preparing magnesium acetyl taurate. Background Art

[0002] Magnesium acetyl taurate is a newly discovered novel pharmaceutical compound with multiple benefits. Existing literature indicates that magnesium acetyl taurate has demonstrated promising results in improving cardiovascular health, alleviating anxiety, and treating neurological disorders.

[0003] Magnesium acetyltaurate is a non-toxic magnesium supplement with minimal side effects. Existing literature indicates that it is effective in maintaining heart rhythm and regulating blood pressure, making it useful in the treatment of cardiovascular disease. Furthermore, existing literature indicates that magnesium acetyltaurate significantly improves the condition of patients with depression and sub-health conditions experiencing significant psychological stress. Furthermore, existing literature indicates that magnesium acetyltaurate has significant potential in treating certain neurodegenerative diseases, such as Alzheimer's disease.

[0004] The synthesis and preparation of magnesium acetyltaurine has always been a difficult problem in this field. In the existing public literature, there are not many documents on the synthesis and preparation of magnesium acetyltaurine. The synthesis route recorded in the synthesis methods recorded in the currently known public literature mainly involves first reacting taurine with magnesium hydroxide to produce magnesium taurine; then acetylating the magnesium taurine to produce magnesium acetyltaurine. For example, the Chinese invention patent with publication number CN112047862A, entitled "A method for preparing magnesium acetyltaurine and its equipment"; and the Chinese invention patent with publication number CN112062696A, entitled "A method for producing magnesium N-acetyltaurine", both adopt the above-mentioned synthesis route. In the prior art, the preparation methods using the above-mentioned synthesis route differ only in the detailed design of the reaction steps and the design of the purification steps. The above-mentioned prior art method mainly considers first preparing magnesium taurate, and the magnesium taurate obtained by acid-base reaction has extremely high purity; then performing acetylation reaction. Under the scale of industrial production, the purity of the obtained magnesium acetyltaurate is guaranteed to a certain extent, and the overall yield is relatively high.

[0005] However, the magnesium acetyl taurate prepared by the existing preparation method still has problems such as relatively insufficient purity and relatively high impurity content when used in the pharmaceutical field. Summary of the Invention

[0006] In order to solve at least one of the above technical problems, a preparation method is developed with relatively low preparation cost, high purity and low impurity content of the prepared magnesium acetyl taurate. The present application provides a preparation method of magnesium acetyl taurate.

[0007] The present application provides a method for preparing magnesium acetyl taurate, comprising the following steps: S1. dissolving taurine in pure water to obtain a taurine solution, and then adding acetic anhydride and mixing thoroughly to obtain a reaction mixture; S2, adding N-acetyltransferase to the reaction mixture obtained in step S1, carrying out acetylation reaction for 4-8 hours, and then concentrating and crystallizing the reaction mixture under reduced pressure to obtain crude acetyltaurine; S3, washing the crude acetyltaurine obtained in step S2 with anhydrous ethanol until there is no residual enzyme, and then heating and drying to obtain pure acetyltaurine; S4, dissolving the pure acetyltaurine obtained in step S3 in water to obtain an acetyltaurine solution, then adding magnesium methoxide, heating to 95-100° C., maintaining the above temperature, heating under reflux for 2-4 hours, and concentrating the reaction solution under reduced pressure and crystallizing to obtain crude magnesium acetyltaurine; S5. Wash the crude magnesium acetyltaurate obtained in step S4 with anhydrous methanol until no magnesium methoxide remains, and then dry it to obtain pure magnesium acetyltaurate.

[0008] Optionally, in step S1, taurine and acetic anhydride are added at a ratio of 9.95 to 10.85 mL of acetic anhydride per 10 g of taurine.

[0009] Optionally, in step S1, the concentration of the prepared taurine solution is controlled to be 40-60 g / L.

[0010] Optionally, in step S2, the amount of N-acetyltransferase added is 4-6 g per 1 L of reaction solution.

[0011] Optionally, in step S2, N-acetyltransferase is used.

[0012] Optionally, in step S2, the reaction temperature of the acetylation reaction is controlled at 30-35° C., and the reaction is carried out under stirring at a speed of 150-300 rpm.

[0013] Optionally, in step S3, the drying temperature of the heating drying is controlled at 145-150°C.

[0014] Optionally, in step S4, acetyltaurine and magnesium methoxide are added in a molar ratio of 2:1.02-1.06.

[0015] Optionally, in step S4, the heating reflux reaction is carried out under stirring at a speed of 30-60 rpm.

[0016] Optionally, in step S5, the drying temperature is controlled at 65-75°C.

[0017] In summary, the present invention includes at least one of the following beneficial technical effects: 1. This application designs a synthetic route for first preparing acetyltaurine and then preparing acetyltaurine magnesium. In the preparation step of acetyltaurine, taurine and acetic anhydride are used as raw materials, and N-acetyltransferase is used as a catalyst to produce extremely high-purity acetyltaurine. In the preparation step of acetyltaurine magnesium, acetyltaurine magnesium is prepared using acetyltaurine prepared in this application and magnesium methoxide as raw materials. The prepared acetyltaurine magnesium has extremely high purity and is very suitable for application in the pharmaceutical field.

[0018] 2. This application uses N-acetyltransferase as a catalyst, taurine and acetic anhydride in a specific feed ratio as raw materials, and has a relatively high reaction yield under the control of specific reaction parameters. At the same time, the N-acetyltransferase and acetic anhydride used are easy to remove, and extremely high-purity acetyltaurine can be produced through simple purification steps.

[0019] 3. This application uses magnesium methoxide and high-purity acetyltaurine prepared in this application as reaction raw materials, and has a relatively high reaction yield under the control of specific reaction parameters; at the same time, the reaction uses water as a solvent carrier, and the magnesium methoxide raw material used can be completely removed with methanol, so that extremely high-purity magnesium acetyltaurate can be produced, effectively avoiding the introduction of impurities.

[0020] 4. The preparation process of this application is relatively simple, the reaction conditions are mild and easy to control, and the reproducibility is good. DETAILED DESCRIPTION

[0021] The following describes the implementation of the present invention using specific embodiments. Those skilled in the art will readily understand the other advantages and benefits of the present invention from the disclosure herein. Obviously, the embodiments described are only a portion of the present invention, not all of it. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0022] The present application provides a method for preparing magnesium acetyl taurate, comprising the following steps: S1. dissolving taurine in pure water to obtain a taurine solution, and then adding acetic anhydride and mixing thoroughly to obtain a reaction mixture; S2, adding N-acetyltransferase to the reaction mixture obtained in step S1, carrying out acetylation reaction for 4-8 hours, and then concentrating and crystallizing the reaction mixture under reduced pressure to obtain crude acetyltaurine; S3, the crude acetyltaurine obtained in step S2 is washed with anhydrous ethanol until there is no residual enzyme, and then heated and dried to obtain pure acetyltaurine; S4, dissolving the pure acetyltaurine obtained in step S3 in water to obtain an acetyltaurine solution, then adding magnesium methoxide, heating to 95-100° C., maintaining the above temperature, heating under reflux for 2-4 hours, and concentrating the reaction solution under reduced pressure and crystallizing to obtain crude magnesium acetyltaurine; S5. Wash the crude magnesium acetyltaurate obtained in step S4 with anhydrous methanol until no magnesium methoxide remains, and then dry it to obtain pure magnesium acetyltaurate.

[0023] Different from the prior art, the synthesis route of the present application adopts a route of first synthesizing acetyltaurine and then synthesizing acetyltaurine magnesium.

[0024] The prior art is based on the consideration of factors such as yield, and most of them adopt the synthetic route of synthesizing magnesium taurine first and then synthesizing magnesium acetyl taurate. Under this synthetic route, the synthesis of magnesium taurine, when produced on a large scale, will have the problem that trace taurine impurities are difficult to remove, and subsequent purification steps also need to add various purification reagents, and then new impurities will be introduced, resulting in the problem of insufficient purity. And when subsequent magnesium acetyl taurate is synthesized, these introduced impurities are also difficult to remove after acetylation reaction, and then the purity of the final magnesium acetyl taurate finished product can only reach 95~98%. For the pharmaceutical field, this purity can only meet basic requirements, and there is a certain impact on the quality of the subsequent prepared medicines.

[0025] The present application is different. The present application adopts an enzyme-catalyzed reaction to first synthesize acetyltaurine, and the yield is slightly lower than that of the prior art. However, when purifying the synthesized acetyltaurine, the residual enzyme can be eliminated by taking advantage of the huge difference in the solubility of acetyltaurine and the enzyme in anhydrous ethanol; and taurine and acetic anhydride can be fed at an oversaturated ratio to ensure that taurine can react completely, and the remaining acetic anhydride impurities can be eliminated by high-temperature drying. The entire reaction design will not introduce any new impurities, and the intermediates obtained can have extremely high purity. In addition, the present application also uses specially designed reaction steps and raw materials to prepare magnesium acetyltaurine, and the reaction design can also ensure that no new impurities are introduced.

[0026] The following are examples of this application The main raw materials used in this application are as follows: Taurine, purity 99.9%, was purchased from Shanghai Jiadeer Chemical Technology Co., Ltd.; acetic anhydride, purity 99.9%, was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd.; N-acetyltransferase, was purchased from Huizhiheyuan Biotechnology (Suzhou) Co., Ltd.; magnesium methoxide, purity 99.9%, was purchased from Jiangsu Pules Biotechnology Co., Ltd.

[0027] Example 1 The preparation method of magnesium acetyl taurate of the present embodiment comprises the following steps: S1. Dissolve 100 g of taurine in pure water to prepare a taurine solution with a concentration of 50 g / L, then add 99.5 mL of acetic anhydride, stir well to mix, and prepare a reaction mixture, which is placed in a constant temperature magnetic stirrer; S2. Add 8 g of N-acetyltransferase to a constant temperature magnetic stirrer, control the reaction temperature to be constant at 30° C., stir at 150 rpm, and perform the acetylation reaction for 8 h. Then, the reaction solution is concentrated under reduced pressure and crystallized to obtain crude acetyltaurine. S3, repeatedly rinsing the crude acetyltaurine obtained in step S2 with anhydrous ethanol until no residual enzyme is left in the rinse residue, then placing the rinsed crude acetyltaurine in a drying oven, heating and drying at 145° C. to constant weight, and cooling to obtain pure acetyltaurine; S4, completely dissolving the pure acetyltaurine obtained in step S3 in water to obtain an acetyltaurine solution, placing the solution in a constant temperature magnetic stirrer, and then adding magnesium methoxide at a molar ratio of 2:1.02 between the pure acetyltaurine and magnesium methoxide; controlling the reaction temperature to be constant at 95° C., stirring at 30 rpm, heating under reflux for 4 h, and concentrating the reaction solution under reduced pressure for crystallization to obtain crude magnesium acetyltaurine; S5. The crude magnesium acetyl taurate obtained in step S4 is repeatedly rinsed with anhydrous methanol until no magnesium methoxide remains in the rinse residue. The washed crude magnesium acetyl taurate is then placed in a drying oven and dried at 65° C. to constant weight. After cooling, pure magnesium acetyl taurate is obtained.

[0028] Example 2 The difference between this embodiment and the first embodiment is that in step S1, 108.5 mL of acetic anhydride is added.

[0029] Example 3 The difference between this embodiment and the second embodiment is that, in step S1, after adding acetic anhydride, ultrasonic mixing is performed for 15 minutes.

[0030] Example 4 The difference between this embodiment and the third embodiment is that in step S2, 10 g of N-acetyltransferase is added.

[0031] Example 5 The difference between this embodiment and the third embodiment is that in step S2, 12 g of N-acetyltransferase is added.

[0032] Example 6 The difference between this embodiment and the fourth embodiment is that in step S2, the reaction temperature is controlled to be constant at 35° C., the stirring speed is 300 rpm, and the acetylation reaction is carried out for 4 hours.

[0033] Example 7 The difference between this embodiment and the fourth embodiment is that in step S2, the reaction temperature is controlled to be constant at 32° C., the stirring speed is 280 rpm, and the acetylation reaction is carried out for 5.5 hours.

[0034] Example 8 The difference between this embodiment and embodiment 7 is that in step S4, magnesium methoxide is added according to a feeding ratio of pure acetyltaurine to magnesium methoxide of 2:1.06.

[0035] Embodiment 9 The difference between this embodiment and the eighth embodiment is that in step S4, the reaction temperature is controlled to be constant at 100° C., the stirring speed is 60 rpm, and the heating reflux reaction is carried out for 2 h.

[0036] Example 10 The difference between this embodiment and the eighth embodiment is that in step S4, the reaction temperature is controlled to be constant at 100° C., the stirring speed is 45 rpm, and the heating reflux reaction is carried out for 2.8 hours.

[0037] Example 11 The difference between this embodiment and the tenth embodiment is that in step S1, the concentration of the prepared taurine solution is 40 g / L.

[0038] Example 12 The difference between this embodiment and the tenth embodiment is that in step S1, the concentration of the prepared taurine solution is 60 g / L.

[0039] Comparative Example 1 The comparative example of the Chinese invention patent with publication number CN112062696A and invention name "Production Method of Magnesium N-Acetyltaurate" is used as comparative example 1 of the present application.

[0040] Comparative Example 2 The difference between this comparative example and Example 10 is that in step S1, 99.0 mL of acetic anhydride was added.

[0041] Comparative Example 3 The difference between this comparative example and Example 10 is that in step S1, 109.0 mL of acetic anhydride is added.

[0042] Testing: Magnesium acetyl taurate was prepared using the preparation methods of Examples 1 to 12 and Comparative Examples 1 to 3 of the present application, with 100 g of taurine as the feed base. The reaction steps were analyzed by HPLC, and the overall yield was calculated. The purity of the obtained magnesium acetyl taurate was also determined by HPLC.

[0043] The test results are shown in Table 1 below.

[0044] Table 1 Test results of examples and comparative examples As can be seen from the data in Table 1, the purity of the magnesium acetyl taurate obtained by the preparation methods of Examples 1 to 12 of the present application is significantly improved compared to the preparation method of Comparative Example 1. The purity of the magnesium acetyl taurate obtained by the preparation method of the present application can reach over 99%, far exceeding the level of 96.44% in Comparative Example 1. The purity of the currently available magnesium acetyl taurate products with higher purity is generally between 98% and 98.5%, which is also significantly lower than the product obtained by the preparation method of the present application.

[0045] A comparison of the data in Table 1, from Example 10 to Comparative Examples 2-3, shows that the feed ratio of taurine to acetic anhydride in the preparation steps of acetyltaurine in this application significantly affects the yield and purity of the application. If the supersaturation rate of acetic anhydride during feeding is too low, the overall yield and purity of the product will be significantly reduced; if the supersaturation rate is too high, the loss of acetyltaurine during purification will result, further reducing the yield.

[0046] From the data comparison of Examples 1 to 12 in Table 1, it can be seen that the preparation method of the present application optimizes the reaction parameters of Step 2 and Step 4 to further improve the overall yield and the purity of the obtained product.

[0047] Purity control in this application focuses on ensuring complete taurine reaction and the presence of residual taurine in the acetyltaurine intermediate during the acetyltaurine preparation step. The feed ratio of taurine to acetic anhydride, reaction parameter control, and enzyme dosage all influence the results of this step. Experimental studies have shown that the overall yield and product purity of the preparation method are optimal under the feed ratio, enzyme dosage, and reaction parameters described in this application.

[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. This 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 techniques in the art not disclosed herein.

Claims

1. A method for preparing magnesium acetyl taurate, characterized in that: The following steps are involved: S1, dissolving taurine in pure water to obtain a taurine solution, and then adding acetic anhydride, mixing well, to obtain a reaction mixture; S2, adding N-acetyltransferase to the reaction mixture obtained in step S1, carrying out acetylation reaction for 4 to 8 hours, and then concentrating and crystallizing the reaction mixture under reduced pressure to obtain crude acetyltaurine; S3, the crude acetyltaurine obtained in step S2 is washed with anhydrous ethanol until there is no residual enzyme, and then subjected to heating and drying treatment to obtain pure acetyltaurine; S4, dissolving the pure acetyltaurine obtained in step S3 in water to obtain an acetyltaurine solution, then adding magnesium methoxide, heating to 95-100° C., maintaining the temperature, heating under reflux for 2-4 hours, and concentrating the reaction solution under reduced pressure to crystallize, to obtain a crude product of magnesium acetyltaurine; S5. The crude magnesium acetyl taurate obtained in step S4 is washed with anhydrous methanol until no magnesium methoxide remains, and then dried to obtain pure magnesium acetyl taurate.

2. The method for preparing magnesium acetyl taurate according to claim 1, wherein In the step S1, taurine and acetic anhydride are added at a ratio of 9.95-10.85 mL of acetic anhydride per 10 g of taurine.

3. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In step S1, the concentration of the prepared taurine solution is controlled at 40-60 g / L.

4. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In the step S2, the amount of N-acetyltransferase added is 4 to 6 g per 1 L of reaction solution.

5. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In the step S2, N-acetyltransferase is used.

6. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In the step S2, the reaction temperature of the acetylation reaction is controlled at 30-35° C., and the reaction is carried out under stirring at a speed of 150-300 rpm.

7. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In step S3, the drying temperature of the heating drying is controlled at 145-150°C.

8. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In the step S4, acetyltaurine and magnesium methoxide are added in a molar ratio of 2:1.02-1.

06.

9. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In the step S4, the heating reflux reaction is carried out under stirring at a speed of 30-60 rpm.

10. The method for preparing magnesium acetyl taurate according to claim 1, characterized in that: In step S5, the drying temperature is controlled at 65-75°C.

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