A kind of preparation method of magnesium acetyl taurate

Abstract

The present application discloses a preparation method of magnesium acetyltaurine, comprising the following steps: S1, taurine solution is configured, and then acetic anhydride is added to obtain a reaction mixture; S2, N-acetyltransferase is added to the reaction mixture, enzyme-catalyzed acetylation reaction, and then concentrated under reduced pressure and crystallized to obtain a crude acetyltaurine product; S3, the crude product is cleaned with anhydrous ethanol, heated and dried, and a pure acetyltaurine product is obtained; S4, acetyltaurine solution is configured, and then magnesium methylate is added, heated to reflux reaction, and then concentrated under reduced pressure and crystallized to obtain a crude acetyltaurine product; S5, the crude product is cleaned with anhydrous methanol, heated and dried, and a pure acetyltaurine product is obtained. The present application has a relatively low preparation cost, and the obtained magnesium acetyltaurine has a high purity and a low impurity content, which is very suitable for the pharmaceutical field.

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 new type of medicinal compound discovered in recent years with multiple functions. According to the existing literature, magnesium acetyl taurate has good effects in improving cardiovascular health, relieving anxiety, and treating neurological diseases.

[0003] Magnesium acetyltaurate is a non-toxic magnesium supplement with extremely low side effects. It is recorded in existing literature that it has a good effect on maintaining heart rhythm and regulating blood pressure, and can be used to treat cardiovascular diseases. At the same time, it is recorded in existing literature that the intake of magnesium acetyltaurate has a significant effect on improving the condition of patients with depression and sub-healthy patients with greater psychological stress. In addition, it is recorded in existing literature that magnesium acetyltaurate has great potential in treating certain neurodegenerative diseases, such as Alzheimer's disease.

[0004] The synthesis and preparation of magnesium acetyl taurate has always been a difficulty in this field. In the existing public documents, there are not many documents on the synthesis and preparation of magnesium acetyl taurate. The synthesis route recorded in the synthesis method recorded in the currently known public documents is mainly to first react taurine with magnesium hydroxide to obtain magnesium taurine; and then acetylate magnesium taurine to obtain magnesium acetyl taurate. For example, the Chinese invention patent with the publication number CN112047862A and the invention name of a preparation method and equipment of magnesium acetyl taurate; and the Chinese invention patent with the publication number CN112062696A and the invention name of the production method of magnesium N-acetyl taurate, all adopt the above-mentioned synthesis route. In the prior art, the preparation method using the above-mentioned synthesis route differs only in the detailed design of the reaction steps and the design of the purification step. The above-mentioned prior art method mainly considers first preparing magnesium taurine, and the magnesium taurine obtained by acid-base reaction has extremely high purity; then an acetylation reaction is carried out. 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 acetyltaurate obtained by the preparation method of the prior art still has problems such as relatively insufficient purity and relatively high impurity content when applied 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 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:

[0008] S1, dissolving taurine in pure water to obtain a taurine solution, and then adding acetic anhydride, mixing well, to obtain a reaction mixture;

[0009] 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;

[0010] 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;

[0011] 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 a crude product of magnesium acetyltaurate;

[0012] 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.

[0013] Optionally, in 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.

[0014] Optionally, in step S1, the concentration of the prepared taurine solution is controlled at 40-60 g / L.

[0015] Optionally, in step S2, the amount of N-acetyltransferase added is 4 to 6 g of N-acetyltransferase per 1 L of reaction solution.

[0016] Optionally, in step S2, N-acetyltransferase is used.

[0017] 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.

[0018] Optionally, in step S3, the drying temperature of the heating drying is controlled at 145-150°C.

[0019] Optionally, in step S4, acetyltaurine and magnesium methoxide are added in a molar ratio of 2:1.02-1.06.

[0020] Optionally, in step S4, the heating reflux reaction is carried out under stirring at a speed of 30-60 rpm.

[0021] Optionally, in step S5, the drying temperature is controlled at 65-75°C.

[0022] In summary, the present invention includes at least one of the following beneficial technical effects:

[0023] 1. The present 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 prepare acetyltaurine with extremely high purity; and in the preparation step of acetyltaurine magnesium, acetyltaurine magnesium is prepared using acetyltaurine prepared in the present application and magnesium methoxide as raw materials, and the prepared acetyltaurine magnesium has extremely high purity and is very suitable for application in the pharmaceutical field.

[0024] 2. This application uses N-acetyltransferase as a catalyst, and uses taurine and acetic anhydride in a specific feed ratio as raw materials. Under the control of specific reaction parameters, it has a relatively high reaction yield; at the same time, the N-acetyltransferase and acetic anhydride used are easy to remove, and extremely high-purity acetyltaurine can be obtained through simple purification steps.

[0025] 3. The present application uses magnesium methoxide and high-purity acetyltaurine prepared in the present 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 obtained, effectively avoiding the introduction of impurities.

[0026] 4. The preparation process of the present application is relatively simple, the reaction conditions are mild and easy to control, and the repeatability is good. DETAILED DESCRIPTION

[0027] 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.

[0028] The present application provides a method for preparing magnesium acetyl taurate, comprising the following steps:

[0029] S1, dissolving taurine in pure water to obtain a taurine solution, and then adding acetic anhydride, mixing well, to obtain a reaction mixture;

[0030] 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;

[0031] 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;

[0032] 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 a crude product of magnesium acetyltaurate;

[0033] 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.

[0034] Different from the prior art, the synthesis route of the present application adopts a route of first synthesizing acetyl taurine and then synthesizing acetyl taurate magnesium.

[0035] 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 the subsequent purification steps also need to add various purification reagents, which will introduce new impurities, resulting in the problem of insufficient purity. And when the subsequent magnesium acetyl taurate is synthesized, these introduced impurities are also difficult to remove after the acetylation reaction, which leads to the purity of the final magnesium acetyl taurate finished product can only reach 95~98%. For the pharmaceutical field, this purity can only meet the basic needs, and there is a certain impact on the quality of the subsequent prepared drugs.

[0036] The present application is different. The present application adopts enzyme catalysis reaction to synthesize acetyltaurine first, and the yield is slightly lower than that of the prior art. However, when acetyltaurine is synthesized and purified, the residual enzyme can be eliminated by taking advantage of the huge difference in solubility between acetyltaurine and enzyme in anhydrous ethanol; and taurine and acetic anhydride can adopt an oversaturated feed 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 new impurities at all, and the intermediate 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.

[0037] The following are examples of the present application:

[0038] The sources of the main raw materials used in the examples of this application are as follows:

[0039] Taurine, purity 99.9%, was purchased from Shanghai Jiader Chemical Technology Co., Ltd.; acetic anhydride, purity 99.9%, was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd.; N-acetyltransferase, was purchased from Huizhi Heyuan Biotechnology (Suzhou) Co., Ltd.; magnesium methoxide, purity 99.9%, was purchased from Jiangsu Pules Biotechnology Co., Ltd.

[0040] Embodiment 1

[0041] The preparation method of magnesium acetyl taurate of the present embodiment comprises the following steps:

[0042] S1, dissolving 100 g of taurine in pure water to prepare a taurine solution with a concentration of 50 g / L, and then adding 99.5 mL of acetic anhydride, stirring and mixing thoroughly to obtain a reaction mixture, which is placed in a constant temperature magnetic stirrer;

[0043] S2, adding 8g of N-acetyltransferase to a constant temperature magnetic stirrer, controlling the reaction temperature to be constant at 30°C, stirring speed to be 150rpm, acetylation reaction for 8h, and then concentrating and crystallizing the reaction solution under reduced pressure to obtain crude acetyltaurine;

[0044] S3, the crude acetyltaurine obtained in step S2 is repeatedly rinsed with anhydrous ethanol until there is no residual enzyme in the residual rinse liquid, and then the rinsed crude acetyltaurine is placed in a drying oven, heated and dried at 145° C. to constant weight, and cooled to obtain pure acetyltaurine;

[0045] 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 hours, and concentrating the reaction solution under reduced pressure and crystallizing to obtain a crude product of magnesium acetyltaurine;

[0046] S5. The crude acetyl taurate magnesium obtained in step S4 is repeatedly rinsed with anhydrous methanol until no magnesium methoxide remains in the residual rinse liquid. The rinsed crude acetyl taurate magnesium is then placed in a drying oven, dried at 65° C. to constant weight, and cooled to obtain pure acetyl taurate magnesium.

[0047] Embodiment 2

[0048] The difference between this embodiment and the first embodiment is that in step S1, 108.5 mL of acetic anhydride is added.

[0049] Embodiment 3

[0050] 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.

[0051] Embodiment 4

[0052] The difference between this embodiment and the third embodiment is that in step S2, 10 g of N-acetyltransferase is added.

[0053] Embodiment 5

[0054] The difference between this embodiment and the third embodiment is that in step S2, 12 g of N-acetyltransferase is added.

[0055] Embodiment 6

[0056] 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.

[0057] Embodiment 7

[0058] 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 h.

[0059] Embodiment 8

[0060] The difference between this embodiment and the seventh embodiment is that in step S4, magnesium methoxide is added according to a feed ratio of pure acetyltaurine to magnesium methoxide of 2:1.06 in molar ratio.

[0061] Embodiment 9

[0062] 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.

[0063] Embodiment 10

[0064] 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 h.

[0065] Embodiment 11

[0066] 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.

[0067] Embodiment 12

[0068] 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.

[0069] Comparative Example 1

[0070] 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.

[0071] Comparative Example 2

[0072] The difference between this comparative example and Example 10 is that in step S1, 99.0 mL of acetic anhydride is added.

[0073] Comparative Example 3

[0074] The difference between this comparative example and Example 10 is that in step S1, 109.0 mL of acetic anhydride is added.

[0075] Detection: Using the preparation methods of Examples 1 to 12 and Comparative Examples 1 to 3 of the present application, 100 g of taurine was used as the feed reference to prepare magnesium acetyl taurate. The reaction steps were detected by HPLC to calculate the total yield of the reaction; the purity of the prepared magnesium acetyl taurate was detected by HPLC.

[0076] The test results are shown in Table 1 below.

[0077] Table 1 Test results of examples and comparative examples

[0078]

[0079] It can be seen from the data in Table 1 that 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 with 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 more than 99%, far exceeding the level of 96.44% in Comparative Example 1. The purity of the magnesium acetyl taurate products with higher purity currently available on the market is basically 98% to 98.5%, which is also significantly lower than the product obtained by the preparation method of the present application.

[0080] From the data in Table 1, it can be seen from the data comparison between Example 10 and Comparative Examples 2 to 3 that in the preparation step of acetyltaurine of the present application, the feed ratio of taurine and acetic anhydride has a great influence on the yield and purity of the present application. When feeding, if the supersaturation rate of acetic anhydride is too low, the overall yield of the present application and the purity of the obtained product will be significantly reduced; if the supersaturation rate is too high, it will lead to the loss of acetyltaurine during purification, thereby reducing the yield.

[0081] 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.

[0082] The core of the purity control of the present application is whether taurine is completely reacted in the acetyltaurine preparation step and whether there is residual taurine mixed in the intermediate product acetyltaurine. The feed ratio of taurine and acetic anhydride, reaction parameter control, and the amount of enzyme added all have an impact on the result of this step; through experimental research, under the conditions of the feed ratio, enzyme addition and reaction parameters of the present application, the overall yield of the preparation method and the purity of the obtained product are relatively optimal.

[0083] 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 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 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 a crude product of magnesium acetyltaurate; S5, washing the crude magnesium acetyl taurate obtained in step S4 with anhydrous methanol until no magnesium methoxide remains, and then drying the crude magnesium acetyl taurate to obtain pure magnesium acetyl taurate; 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; in the step S1, the concentration of the prepared taurine solution is controlled at 40-60 g / L; In the step S2, the amount of N-acetyltransferase added is 4-6 g of N-acetyltransferase per 1 L of reaction solution; in the step S2, the reaction temperature of the acetylation reaction is controlled at 30-35° C.; In the step S4, acetyltaurine and magnesium methoxide are added in a molar ratio of 2:1.02-1.

06.

2. The method for preparing magnesium acetyl taurate according to claim 1, wherein In the step S2, the reaction is carried out under stirring at a speed of 150-300 rpm.

3. 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.

4. 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.

5. 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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