A methyl 5-aminolevulinate hydrochloride and its preparation method

Abstract

This application provides a method for preparing methyl 5-aminolevulinate hydrochloride and the same, relating to the field of methyl 5-aminolevulinate hydrochloride preparation technology. Methanol is added to a reaction vessel, the temperature is lowered to 0-10°C, and thionyl chloride is added dropwise under controlled temperature. After the addition is complete, the mixture is kept at a constant temperature and stirred to obtain a reaction solution. The pH of the reaction solution is controlled to 1.5-2.5 by vacuum distillation. 5-aminolevulinate salt is added to the reaction solution, the temperature is raised to 60-65°C, and the mixture is refluxed and stirred. A crystallization promoter is added to the system, and crystallization is stirred, filtered, and dried to obtain methyl 5-aminolevulinate hydrochloride. The preparation method of this application allows for sufficient contact between the components in the reaction system, while effectively controlling side reactions and reverse reactions. The purity of the obtained product can reach over 99%, and the yield can reach over 84%. This overcomes the high energy consumption problem caused by traditional high-temperature reactions, significantly reducing energy consumption and production costs.

Description

Technical Field

[0001] This application relates to the field of methyl 5-aminolevulinate hydrochloride preparation technology, and in particular to a methyl 5-aminolevulinate hydrochloride and its preparation method. Background Technology

[0002] 5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid that participates in the synthesis of heme and chlorophyll in organisms. In recent years, 5-ALA and its derivatives have shown broad application prospects in medicine, agriculture, and other fields.

[0003] 5-Aminolevulinic acid methyl ester hydrochloride (5-ALA-ME) is an ester derivative of 5-ALA. Compared to 5-ALA, it is more lipid-soluble and more easily permeates cell membranes, thus having advantages in certain applications.

[0004] The traditional method for synthesizing 5-ALA-ME involves using 5-aminolevulinate as a raw material, undergoing an etherification reaction in methanol catalyzed by 3A or 4A aluminosilicate molecular sieves, followed by high-temperature drying at 300-350°C. However, this traditional synthesis technique suffers from drawbacks such as demanding control conditions, high reaction temperatures, high energy consumption, and high production costs. Summary of the Invention

[0005] To address the problems of stringent control conditions, high reaction temperatures, high energy consumption, and high production costs in existing methods for synthesizing 5-ALA-ME, this application provides a methyl 5-aminolevulinate hydrochloride and its preparation method.

[0006] In a first aspect, this application provides a method for preparing methyl 5-aminolevulinate hydrochloride, employing the following technical solution:

[0007] A method for preparing methyl 5-aminolevulinate hydrochloride includes the following steps:

[0008] Step S101: Add methanol to the reaction vessel, cool to 0-10°C, add thionyl chloride dropwise under controlled temperature, and stir while keeping warm after the addition is complete to obtain a reaction solution. Then, perform vacuum distillation to control the pH value of the reaction solution to 1.5-2.5.

[0009] Step S102: Add 5-aminolevulinic acid salt to the reaction solution of step S101. After the addition is complete, heat to 60-65°C and reflux with stirring.

[0010] Step S103: Add crystallization promoter to the system in step S102. After the addition is complete, stir to induce crystallization, filter, and dry to obtain methyl 5-aminolevulinate hydrochloride.

[0011] This application involves pre-reacting methanol with thionyl chloride at low temperature. The hydroxyl group of methanol undergoes a nucleophilic substitution reaction with the chlorine atom of thionyl chloride to generate the intermediate methyl sulfite chloride, releasing hydrogen chloride in the process. Then, methyl sulfite chloride reacts with 5-aminolevulinate hydrochloride. The -OSOCl group in methyl sulfite chloride undergoes a nucleophilic substitution reaction with the carboxylic acid group in 5-aminolevulinate hydrochloride to form an ester bond, releasing sulfur dioxide and hydrogen chloride in the process. Due to the high reactivity of methyl sulfite chloride, its -OSOCl group readily leaves, making the esterification reaction easier and achieving higher yields and reaction rates. Furthermore, the two oxygen atoms on the final product, methyl 5-aminolevulinate hydrochloride, originate from carboxylic acids, unlike in traditional esterification reactions where they originate from alcohols and carboxylic acids respectively. Therefore, methanol does not directly participate in ester bond formation, reducing side reaction pathways and improving product selectivity.

[0012] In step S101, a large amount of HCl is generated during the reaction of thionyl chloride and methanol, creating a strongly acidic environment in the reaction solution. In subsequent step S102, when 5-aminolevulinic acid salt is added and the temperature is increased, the ester bond of methyl 5-aminolevulinic acid hydrochloride is easily hydrolyzed acidically, reverting to a carboxylic acid. Therefore, this application removes free HCl from the system by vacuum distillation, reducing the H2 content in the system. + The concentration is adjusted to control the pH of the reaction solution to 1.5–2.5, which greatly avoids the hydrolysis of the reaction product methyl 5-aminolevulinate hydrochloride in step S102 during reflux stirring.

[0013] Moreover, removing free HCl from the system by vacuum distillation does not introduce new impurities into the system, promotes the forward reaction, and inhibits side reactions, thus significantly improving the reaction yield and product purity.

[0014] Optionally, the temperature of the vacuum distillation process is 30–40°C, and the vacuum degree is 0.08–0.09 MPa.

[0015] By adopting the above technical solutions, free HCl in the reaction solution can be removed without introducing impurities, providing a non-acidic environment for subsequent reactions and avoiding product hydrolysis.

[0016] Optionally, the crystallization promoter is methyl tert-butyl ether, tetrahydrofuran, or methyltetrahydrofuran.

[0017] By limiting the crystallization promoters to the types described above, the crystallization promoters can facilitate the precipitation of the product from the solution, effectively reduce the solubility of the product in the solvent, promote the selective precipitation of the target product, and reduce the co-crystallization of impurities.

[0018] Optionally, the crystallization temperature in step S103 is 0–30°C.

[0019] Optionally, the crystallization temperature in step S103 is 0–15°C.

[0020] Optionally, the crystallization temperature in step S103 is 0°C.

[0021] By limiting the crystallization temperature, the solubility of the product in the solvent is reduced, which promotes rapid crystal nucleation and the formation of small-sized uniform crystals.

[0022] Optionally, 5 to 11 ml of crystallization promoter may be added to each 1 g of 5-aminolevulinate.

[0023] Optionally, 8–11 ml of crystallization promoter may be added to each 1 g of 5-aminolevulinate salt.

[0024] Optionally, 11 ml of crystallization promoter may be added to each 1 g of 5-aminolevulinate salt.

[0025] By limiting the ratio of raw materials to crystallization promoters, it is possible to ensure that impurities are fully dissolved in the solvent and maintain a reasonable crystallization rate, thereby improving the purity of the product.

[0026] Optionally, the mass ratio of the 5-aminolevulinate salt to the thionyl chloride is 1:0.9 to 1.

[0027] Optionally, the mass ratio of the 5-aminolevulinate salt to the thionyl chloride is 1:0.92.

[0028] By limiting the amount of thionyl chloride used, the amount of HCl produced can be reduced while ensuring complete conversion of carboxylic acids, thus balancing the completeness of the reaction with the risk of side reactions.

[0029] Optionally, 2 to 3 ml of methanol may be used per 1 g of 5-aminolevulinate.

[0030] Optionally, 2.5 ml of methanol may be used for every 1 g of 5-aminolevulinate.

[0031] By limiting the amount of methanol used as described above, a sufficient solvation environment can be provided to promote the reaction. At the same time, the high concentration of methanol promotes the esterification reaction in the forward direction and reduces the hydrolysis of ester bonds.

[0032] Optionally, the method further includes a step of purifying the methyl 5-aminolevulinate hydrochloride, specifically as follows: Step S104: Dissolve the methyl 5-aminolevulinate hydrochloride obtained in step S103 in methanol, then add acetone dropwise to it. After the addition is complete, lower the internal temperature to 0-10°C, stir to precipitate crystals, then filter, wash the filter cake with acetone, and finally vacuum dry the filter cake to obtain the final product.

[0033] Optionally, the temperature of the vacuum drying process in step S104 is 50-60°C, and the vacuum degree is ≤-0.09MPa.

[0034] The above purification steps utilize methanol to dissolve the product and remove insoluble impurities, while acetone acts as an antisolvent to reduce solubility and promote crystallization of the target product. This process can remove trace impurities remaining during the initial crystallization process and improve product purity.

[0035] Secondly, this application provides a methyl 5-aminolevulinate hydrochloride, prepared by the above-described preparation method.

[0036] The product methyl 5-aminolevulinate hydrochloride obtained by the above preparation method has a high purity of over 99%, and the product yield can reach over 84%.

[0037] In summary, this application includes at least one of the following beneficial effects:

[0038] 1. This application involves reacting methanol with thionyl chloride at low temperature to generate the intermediate methyl sulfite chloride, which is then reacted with 5-aminolevulinate hydrochloride to finally obtain the product methyl 5-aminolevulinate hydrochloride. This preparation method overcomes the high energy consumption problem caused by traditional high-temperature reactions and significantly reduces energy consumption and production costs.

[0039] 2. The preparation method provided in this application enables the components in the reaction system to fully contact and react, while effectively controlling side reactions and reverse reactions. The purity of the obtained product can reach more than 99%, and the yield can reach more than 84%. Attached Figure Description

[0040] Figure 1 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 1;

[0041] Figure 2 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 2;

[0042] Figure 3 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 3;

[0043] Figure 4This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 4;

[0044] Figure 5 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 5;

[0045] Figure 6 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 6;

[0046] Figure 7 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 7;

[0047] Figure 8 This is the high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Comparative Example 1;

[0048] Figure 9 This is the high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Comparative Example 2;

[0049] Figure 10 This is a high-performance liquid chromatogram of methyl 5-aminolevulinate hydrochloride prepared in Example 8. Detailed Implementation

[0050] This application provides a method for preparing methyl 5-aminolevulinate hydrochloride, comprising the following steps: Step S101: Add methanol to a reaction vessel, cool to 0-10°C, add thionyl chloride dropwise under controlled temperature, and after the addition is complete, keep warm and stir to obtain a reaction solution, and then perform vacuum distillation to control the pH value of the reaction solution to 1.5-2.5.

[0051] Step S102: Add 5-aminolevulinic acid salt to the reaction solution of step S101. After the addition is complete, heat to 60-65°C and reflux with stirring.

[0052] Step S103: Add crystallization promoter to the system in step S102. After the addition is complete, stir to induce crystallization, filter, and dry to obtain methyl 5-aminolevulinate hydrochloride.

[0053] The reaction principle involved in the above preparation method is as follows:

[0054]

[0055] The technical solution of the present invention will be further explained and described below with reference to specific embodiments and accompanying drawings. It should be noted that the specific embodiments presented herein are only intended to aid in understanding the present invention and are not intended to constitute a specific limitation thereof. Unless otherwise stated, the raw materials selected in the embodiments of the present invention are all commonly used in the art.

[0056] Example 1

[0057] Example 1 provides a method for preparing methyl 5-aminolevulinate hydrochloride, the specific steps of which are as follows:

[0058] (1) Measure 250.0 ml of methanol and add it to a 2000 ml three-necked flask. Use an ice-water bath to lower the internal temperature to 0℃ and control the internal temperature to 0℃. Add 92.00 g of thionyl chloride dropwise to the three-necked flask. After the addition is complete, keep it warm and stir in an ice-water bath at 0℃. After stirring and reacting for 1 h, the reaction solution is obtained. Then, the reaction solution is subjected to vacuum distillation treatment, with the vacuum degree controlled at 0.08 MPa and the temperature at 40℃. During this process, the pH value of the reaction solution is detected. When the pH value rises to 1.5, the vacuum distillation treatment is stopped, and 100 ml of methanol is added at the same time.

[0059] (2) Add 100.00g of 5-aminolevulinate salt to the reaction solution. After the addition is complete, heat the solution to 60℃ and reflux for 3 hours.

[0060] (3) Finally, add 1100.0 ml of methyl tert-butyl ether. After the addition is complete, maintain the internal temperature at 0℃ and stir to allow crystallization for 3 hours. Filter, wash the filter cake with a small amount of methyl tert-butyl ether, and dry to obtain methyl 5-aminolevulinate hydrochloride with a purity of 99.741% and a molar yield of 90%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 1 As shown.

[0061] Example 2

[0062] Example 2 is basically the same as Example 1, except that the amount of methyl tert-butyl ether added in Example 2 is 800.0 ml.

[0063] The purity of the crude 5-ALA-ME obtained in this example was 99.634%, and the molar yield was 84%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 2 As shown.

[0064] Example 3

[0065] Example 3 is basically the same as Example 1, except that the amount of methyl tert-butyl ether added in Example 3 is 500.0 ml.

[0066] The purity of the crude 5-ALA-ME obtained in this example was 99.593%, and the molar yield was 76%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 3 As shown.

[0067] Example 4

[0068] Example 4 is basically the same as Example 1, except that the crystallization temperature in Example 4 is 15°C.

[0069] The purity of the crude 5-ALA-ME obtained in this example was 99.735%, and the molar yield was 86%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 4 As shown.

[0070] Example 5

[0071] Example 5 is basically the same as Example 1, except that the crystallization temperature in Example 5 is 30°C.

[0072] The purity of the crude 5-ALA-ME obtained in this example was 99.704%, and the molar yield was 85%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 5 As shown.

[0073] Example 6

[0074] Example 6 is basically the same as Example 1, except that in Example 6, an equal volume of tetrahydrofuran is used instead of methyl tert-butyl ether.

[0075] The purity of the crude 5-ALA-ME obtained in this example was 99.596%, and the molar yield was 85%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 6 As shown.

[0076] Example 7

[0077] Example 7 is basically the same as Example 1, except that in Example 7, an equal volume of methyltetrahydrofuran is used instead of methyl tert-butyl ether.

[0078] The purity of the crude 5-ALA-ME obtained in this example was 99.732%, and the molar yield was 87%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 7 As shown.

[0079] Comparative Example 1

[0080] Comparative Example 1 is basically the same as Example 1, except that the reaction solution was not subjected to vacuum distillation in step S101 in Comparative Example 1.

[0081] The purity of the crude 5-ALA-ME obtained in this example was 96.746%, and the molar yield was 69%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 8 As shown.

[0082] Comparative Example 2

[0083] Comparative Example 2 is basically the same as Example 1, except that in Comparative Example 1, an equal volume of dichloromethane is used instead of methyl tert-butyl ether.

[0084] The purity of the crude 5-ALA-ME obtained in this example was 99.824%, and the molar yield was 54%. The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this example is shown below. Figure 9 As shown.

[0085] Example 8

[0086] Example 8 provides a method for preparing methyl 5-aminolevulinate hydrochloride, the specific steps of which are as follows:

[0087] (1) Weigh 90.00g of 5-ALA-ME prepared in Example 1 and 113.0ml of methanol, add them to a 2000ml three-necked flask, and heat in a water bath until dissolved under reflux with stirring.

[0088] (2) After dissolution, add 1350.0 ml of acetone to the three-necked flask. After the addition is complete, cool the internal temperature to 10°C and stir to allow crystals to precipitate for 2 hours.

[0089] (3) Filter the filter cake and wash it with a small amount of acetone to obtain 5-ALA-ME wet product;

[0090] (4) Place the wet 5-ALA-ME in a vacuum oven, control the temperature at 60℃ and the vacuum degree at ≤-0.09MPa, and vacuum dry until the rapid drying loss is ≤0.2%, to obtain 79g of dry 5-ALA-ME with a purity of 99.893% and a yield of 88%.

[0091] The HPLC chromatogram of the methyl 5-aminolevulinate hydrochloride prepared in this embodiment is shown below. Figure 10 As shown.

[0092] In summary, this application further optimizes the type and amount of crystallization promoter and the crystallization temperature, thereby obtaining a method for preparing methyl 5-aminolevulinate hydrochloride with a low reaction temperature, and the obtained methyl 5-aminolevulinate hydrochloride product has high purity and high yield.

[0093] The above are all preferred embodiments of this application, and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made in accordance with the structure, shape and principle of this application should be covered within the scope of protection of this application.

Claims

1. A process for the preparation of 5-amino levulinic acid methyl ester hydrochloride, characterized in that, The method comprises the following steps: Step S101: adding methanol into a reaction container, cooling to 0-10℃, adding dropwise chlorosulfuric acid under temperature control, after the dropwise addition is completed, the reaction liquid is obtained by incubation and stirring, and then the reaction liquid is treated by vacuum distillation to control the pH value to 1.5-2.5; Step S102: adding 5-amino levulinic acid hydrochloride into the reaction liquid of step S101, after the addition is completed, heating to 60-65℃, and then treating by refluxing and stirring; Step S103: adding a crystallization promoter into the system of step S102, after the addition is completed, stirring and crystallizing, filtering, and drying to obtain 5-amino levulinic acid methyl ester hydrochloride, wherein the crystallization promoter is methyl tert-butyl ether, tetrahydrofuran or methyl tetrahydrofuran.

2. The process for preparing 5-amino levulinic acid methyl ester hydrochloride according to claim 1, characterized in that, The temperature of the vacuum distillation treatment is 30-40℃, and the vacuum degree is 0.08-0.09 MPa.

3. The method for preparing methyl 5-aminolevulinate hydrochloride according to claim 1, characterized in that, The crystallization temperature in step S103 is 0-30℃.

4. The method for preparing methyl 5-aminolevulinate hydrochloride according to claim 1, characterized in that, 5-11 ml of the crystallization promoter is added per 1 g of 5-amino levulinic acid hydrochloride.

5. The method for preparing methyl 5-aminolevulinate hydrochloride according to claim 1, characterized in that, The mass ratio of the 5-amino levulinic acid hydrochloride to the chlorosulfuric acid is 1:0.9-1.

6. The method for preparing methyl 5-aminolevulinate hydrochloride according to claim 1, characterized in that, 2-3 ml of methanol is used per 1 g of 5-amino levulinic acid hydrochloride.

7. The method for preparing methyl 5-aminolevulinic acid hydrochloride according to claim 1, characterized in that, The method further comprises a step of purifying the 5-amino levulinic acid methyl ester hydrochloride, specifically as follows, Step S104: dissolving the 5-amino levulinic acid methyl ester hydrochloride obtained in step S103 in methanol, then adding dropwise acetone, after the dropwise addition is completed, reducing the internal temperature to 0-10℃, stirring and crystallizing, then filtering, using acetone to rinse the filter cake, and finally performing vacuum drying treatment on the filter cake to obtain the product.

8. The method for preparing methyl 5-aminolevulinate hydrochloride according to claim 7, characterized in that, The temperature of the vacuum drying treatment in step S104 is 50-60℃, and the vacuum degree is ≤-0.09 MPa.

Images