Methyl 5-aminolevulinate hydrochloride and preparation method thereof

Abstract

The invention provides 5-aminolevulinic acid methyl ester hydrochloride and a preparation method thereof, and relates to the technical field of preparation of 5-aminolevulinic acid methyl ester hydrochloride. The method comprises the following steps: adding methanol into a reaction container, cooling to 0-10 DEG C, dropwise adding thionyl chloride under temperature control, after dropwise adding is completed, carrying out heat preservation and stirring to obtain a reaction solution, and carrying out reduced pressure distillation treatment to control the pH value of the reaction solution to 1.5-2.5; adding 5-aminolevulinic acid hydrochloride into the reaction liquid, heating to 60-65 DEG C, and carrying out reflux stirring treatment; and adding a crystallization accelerant into the system, stirring for crystallization, filtering and drying to obtain the 5-aminolevulinic acid methyl ester hydrochloride. According to the preparation method disclosed by the invention, all components in a reaction system can be in full contact for reaction, meanwhile, side reaction and reverse reaction are effectively controlled, the purity of the obtained product can reach 99% or above, the yield can reach 84% or above, the problem of high energy consumption caused by traditional high-temperature reaction is solved, and energy consumption and production cost are remarkably reduced.

Description

Technical Field

[0001] The present application relates to the technical field of preparation of 5-aminolevulinic acid methyl ester hydrochloride, and in particular to 5-aminolevulinic acid methyl ester hydrochloride and a preparation method thereof. Background Art

[0002] 5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid that participates in the synthesis of hemoglobin and chlorophyll in living 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 with 5-ALA, it is more lipid-soluble and easier to pass through cell membranes, so it has advantages in certain applications.

[0004] The traditional method for synthesizing 5-ALA-ME uses 5-aminolevulinic acid hydrochloride as the raw material, and conducts an etherification reaction in methanol catalyzed by 3A or 4A aluminosilicate molecular sieves under high-temperature drying conditions of 300-350°C. However, this traditional synthesis technology suffers from stringent control conditions, high reaction temperatures, high energy consumption, and high production costs. Summary of the Invention

[0005] In order to improve the problems of the existing method for synthesizing 5-ALA-ME, such as harsh control conditions, high reaction temperature, high energy consumption and high production cost, the present application provides 5-aminolevulinic acid methyl ester hydrochloride and a preparation method thereof.

[0006] In a first aspect, the present application provides a method for preparing methyl 5-aminolevulinate hydrochloride, which adopts the following technical solution: A method for preparing methyl 5-aminolevulinate hydrochloride comprises the following steps: Step S101: adding methanol to a reaction vessel, cooling the temperature to 0-10° C., adding thionyl chloride dropwise under temperature control, and stirring the mixture to obtain a reaction solution after the addition is complete. The mixture is then subjected to reduced pressure distillation to control the pH value of the reaction solution to 1.5-2.5; Step S102: adding 5-aminolevulinic acid hydrochloride to the reaction solution of step S101, heating to 60-65° C. after the addition is complete, and performing reflux stirring; Step S103: adding a crystallization accelerator to the system of step S102, stirring and crystallizing after the addition is completed, filtering, and drying to obtain 5-aminolevulinic acid methyl ester hydrochloride.

[0007] The present application is to react methanol with thionyl chloride in advance, and the hydroxyl group of methanol undergoes a nucleophilic substitution reaction with the chlorine atom of thionyl chloride under low temperature conditions to generate an intermediate methyl chloride sulfite, while releasing hydrogen chloride; then the methyl chloride sulfite reacts with 5-aminolevulinic acid hydrochloride, and the group -OSOCl in the methyl chloride sulfite undergoes a nucleophilic substitution reaction with the carboxylic acid group in the 5-aminolevulinic acid hydrochloride to form an ester bond, while releasing sulfur dioxide and hydrogen chloride. Since methyl chloride sulfite is highly reactive, its -OSOCl group is easy to leave, thereby making the esterification reaction easier, thereby achieving a higher yield and reaction rate. Moreover, the two oxygen atoms on the final product 5-aminolevulinic acid methyl ester hydrochloride are both from carboxylic acid, rather than from alcohol and carboxylic acid as in the traditional esterification reaction, so methanol does not directly participate in the ester bond formation, the side reaction path is reduced, and the product selectivity is improved.

[0008] In step S101, a large amount of HCl is generated during the reaction of thionyl chloride and methanol, thus forming a strong acidic environment in the reaction solution. In the subsequent step S102, when 5-aminolevulinic acid hydrochloride is added and the temperature is raised, the ester bond of 5-aminolevulinic acid methyl ester hydrochloride is easily hydrolyzed by acid and converted into carboxylic acid. Therefore, the present invention adopts a vacuum distillation method to remove free HCl in the system and reduce the HCl in the system. + The concentration is adjusted to control the pH value of the reaction solution to 1.5-2.5, thereby greatly avoiding the hydrolysis of the reaction product 5-aminolevulinic acid methyl ester hydrochloride in step S102 during the reflux stirring process.

[0009] Moreover, the use of reduced pressure distillation to remove free HCl in the system does not introduce new impurities into the system, promotes the forward progress of the reaction, and inhibits the occurrence of side reactions, thereby significantly improving the reaction yield and product purity.

[0010] Optionally, the temperature of the reduced pressure distillation treatment is 30-40° C., and the vacuum degree is 0.08-0.09 MPa.

[0011] By adopting the above technical solution, free HCl in the reaction solution can be removed without introducing impurities, providing a non-overacidic environment for subsequent reactions and avoiding product hydrolysis.

[0012] Optionally, the crystallization promoter is methyl tert-butyl ether, tetrahydrofuran or methyltetrahydrofuran.

[0013] By limiting the types of crystallization promoters as described above, the crystallization promoters can precipitate 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.

[0014] Optionally, the crystallization temperature in step S103 is 0-30°C.

[0015] Optionally, the crystallization temperature in step S103 is 0-15°C.

[0016] Optionally, the crystallization temperature in step S103 is 0°C.

[0017] By limiting the above-mentioned crystallization temperature, the solubility of the product in the solvent is reduced, which can promote the rapid nucleation of crystals and form small-sized uniform crystals.

[0018] Optionally, 5 to 11 ml of a crystallization accelerator is added to every 1 g of 5-aminolevulinic acid hydrochloride.

[0019] Optionally, 8 to 11 ml of a crystallization accelerator is added to every 1 g of 5-aminolevulinic acid hydrochloride.

[0020] Optionally, 11 ml of a crystallization accelerator is added to every 1 g of 5-aminolevulinic acid hydrochloride.

[0021] 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.

[0022] Optionally, the mass ratio of the 5-aminolevulinic acid hydrochloride to the thionyl chloride is 1:0.9-1.

[0023] Optionally, the mass ratio of the 5-aminolevulinic acid hydrochloride to the thionyl chloride is 1:0.92.

[0024] By limiting the amount of thionyl chloride used, the amount of HCl generated can be reduced while ensuring complete conversion of the carboxylic acid, thus balancing the completeness of the reaction with the risk of side reactions.

[0025] Alternatively, 2 to 3 ml of methanol is used per 1 g of 5-aminolevulinic acid hydrochloride.

[0026] Alternatively, 2.5 ml of methanol was used per 1 g of 5-aminolevulinic acid hydrochloride.

[0027] By limiting the amount of methanol as mentioned above, a sufficient solvent environment can be provided to promote the reaction. At the same time, high concentration of methanol promotes the esterification reaction to proceed in the forward direction and reduces the hydrolysis of the ester bond.

[0028] Optionally, the method further includes a step of purifying the 5-aminolevulinic acid methyl ester hydrochloride, specifically as follows: step S104: dissolving the 5-aminolevulinic acid methyl ester hydrochloride obtained in step S103 in methanol, and then adding acetone dropwise thereto. After the addition is completed, the internal temperature is cooled to 0-10° C., stirred for crystallization, and then filtered. The filter cake is rinsed with acetone, and finally the filter cake is vacuum dried to obtain the product.

[0029] Optionally, the temperature of the vacuum drying treatment in step S104 is 50-60° C., and the vacuum degree is ≤-0.09 MPa.

[0030] The above purification step utilizes methanol to dissolve the product and remove insoluble impurities, and acetone is used as an anti-solvent to reduce the solubility and promote crystallization of the target product, thereby removing trace impurities remaining in the initial crystallization process and improving the product purity.

[0031] In a second aspect, the present application provides methyl 5-aminolevulinate hydrochloride, which is prepared by the above-mentioned preparation method.

[0032] The product 5-aminolevulinic acid methyl ester hydrochloride obtained by the above preparation method has a high purity of more than 99%, and the product yield can reach more than 84%.

[0033] In summary, this application has at least one of the following beneficial effects: 1. The present application prepares 5-aminolevulinic acid methyl ester hydrochloride by reacting methanol with thionyl chloride at low temperature in advance to generate an intermediate methyl chloride sulfite, which is then reacted with 5-aminolevulinic acid hydrochloride to finally obtain the product 5-aminolevulinic acid methyl ester hydrochloride. This preparation method overcomes the high energy consumption problem caused by traditional high-temperature reactions and significantly reduces energy consumption and production costs.

[0034] 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%. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 1; Figure 2 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 2; Figure 3 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 3; Figure 4 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 4; Figure 5is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 5; Figure 6 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 6; Figure 7 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 7; Figure 8 This is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Comparative Example 1; Figure 9 This is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Comparative Example 2; Figure 10 1 is a high performance liquid chromatogram of 5-aminolevulinic acid methyl ester hydrochloride prepared in Example 8. DETAILED DESCRIPTION

[0036] The present embodiment provides a method for preparing methyl 5-aminolevulinate hydrochloride, comprising the following steps: Step S101: adding methanol to a reaction vessel, cooling the temperature to 0-10° C., adding thionyl chloride dropwise under temperature control, and after the addition is complete, stirring and preserving the temperature to obtain a reaction solution, followed by vacuum distillation to control the pH value of the reaction solution to 1.5-2.5; Step S102: adding 5-aminolevulinic acid hydrochloride to the reaction solution of step S101, heating to 60-65° C. after the addition is complete, and performing reflux stirring; Step S103: adding a crystallization accelerator to the system of step S102, stirring and crystallizing after the addition is completed, filtering, and drying to obtain 5-aminolevulinic acid methyl ester hydrochloride.

[0037] The reaction principle involved in the above preparation method is as follows:

[0038] The technical solutions of the present invention will be further explained and illustrated below in conjunction with specific embodiments and drawings. It should be understood that the specific embodiments presented herein are intended only to facilitate understanding of the present invention and do not constitute specific limitations on the present invention. Unless otherwise specified, the raw materials used in the embodiments of the present invention are all commonly used raw materials in this field.

[0039] Example 1 Example 1 provides a method for preparing 5-aminolevulinic acid methyl ester hydrochloride, the specific steps are as follows: (1) 250.0 ml of methanol was measured and added to a 2000 ml three-necked flask. The internal temperature was lowered to 0°C in an ice-water bath. The internal temperature was controlled at 0°C. 92.00 g of thionyl chloride was added dropwise to the three-necked flask. After the addition was completed, the flask was kept warm and stirred in an ice-water bath at 0°C. After stirring for 1 hour, a reaction solution was obtained. The reaction solution was then subjected to vacuum distillation treatment. The vacuum degree was controlled at 0.08 MPa and the temperature was 40°C. During this process, the pH value of the reaction solution was detected. When the pH value increased to 1.5, the vacuum distillation treatment was stopped and 100 ml of methanol was added at the same time. (2) Add 100.00 g of 5-aminolevulinic acid hydrochloride to the reaction solution, and after the addition is complete, heat to 60° C. and reflux with stirring for 3 h; (3) Finally, 1100.0 ml of methyl tert-butyl ether was added. After the addition was complete, the internal temperature was maintained at 0° C. and stirred for crystallization for 3 h. The mixture was filtered, and the filter cake was rinsed with a small amount of methyl tert-butyl ether and dried to obtain 5-aminolevulinic acid methyl ester hydrochloride with a purity of 99.741% and a molar yield of 90%. The HPLC chart of 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is shown in FIG. Figure 1 shown.

[0040] Example 2 Example 2 is substantially the same as Example 1, except that the amount of methyl tert-butyl ether added in Example 2 is 800.0 ml.

[0041] The purity of the crude 5-ALA-ME obtained in this example is 99.634%, and the molar yield is 84%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 2 shown.

[0042] Example 3 Example 3 is substantially the same as Example 1, except that the amount of methyl tert-butyl ether added in Example 3 is 500.0 ml.

[0043] The purity of the crude 5-ALA-ME obtained in this example is 99.593%, and the molar yield is 76%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 3 shown.

[0044] Example 4 Example 4 is substantially the same as Example 1, except that the crystallization temperature in Example 4 is 15°C.

[0045] The purity of the crude 5-ALA-ME obtained in this example is 99.735%, and the molar yield is 86%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 4 shown.

[0046] Example 5 Example 5 is substantially the same as Example 1, except that the crystallization temperature in Example 5 is 30°C.

[0047] The purity of the crude 5-ALA-ME obtained in this example is 99.704%, and the molar yield is 85%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 5 shown.

[0048] Example 6 Example 6 is substantially the same as Example 1, except that an equal volume of tetrahydrofuran is used to replace methyl tert-butyl ether in Example 6.

[0049] The purity of the crude 5-ALA-ME obtained in this example is 99.596%, and the molar yield is 85%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 6 shown.

[0050] Example 7 Example 7 is substantially the same as Example 1, except that an equal volume of methyltetrahydrofuran is used to replace methyl tert-butyl ether in Example 7.

[0051] The purity of the crude 5-ALA-ME obtained in this example is 99.732%, and the molar yield is 87%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 7 shown.

[0052] Comparative Example 1 Comparative Example 1 is substantially the same as Example 1, except that in Comparative Example 1, the reaction liquid is not subjected to reduced pressure distillation in step S101.

[0053] The purity of the crude 5-ALA-ME obtained in this example is 96.746%, and the molar yield is 69%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 8 shown.

[0054] Comparative Example 2 Comparative Example 2 is substantially the same as Example 1, except that an equal volume of dichloromethane is used in place of methyl tert-butyl ether in Comparative Example 1.

[0055] The purity of the crude 5-ALA-ME obtained in this example is 99.824%, and the molar yield is 54%. The HPLC chart of the 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 9 shown.

[0056] Example 8 Example 8 provides a method for preparing 5-aminolevulinic acid methyl ester hydrochloride, and the specific operations are as follows: (1) Weigh 90.00 g of 5-ALA-ME prepared in Example 1 and 113.0 ml of methanol, add them to a 2000 ml three-necked flask, heat in a water bath until reflux, and stir to dissolve; (2) After dissolution is complete, add 1350.0 ml of acetone dropwise to the three-necked flask. After the addition is complete, cool the internal temperature to 10°C and stir to crystallize for 2 h. (3) Filter and rinse the filter cake with a small amount of acetone to obtain a wet product of 5-ALA-ME; (4) The wet 5-ALA-ME product was placed in a vacuum oven, the temperature was controlled at 60°C, the vacuum degree was ≤-0.09 MPa, and vacuum dried to a fast drying loss of ≤0.2% to obtain 79 g of dry 5-ALA-ME with a purity of 99.893% and a yield of 88%.

[0057] The HPLC chart of 5-aminolevulinic acid methyl ester hydrochloride prepared in this example is as follows: Figure 10 shown.

[0058] In summary, the present application further optimizes the type and dosage of the crystallization promoter and the crystallization temperature, thereby obtaining a method for preparing 5-aminolevulinic acid methyl ester hydrochloride with a low reaction temperature, and the obtained 5-aminolevulinic acid methyl ester hydrochloride product has high purity and high yield.

[0059] The above are all preferred embodiments of the present application, and are not intended to limit the scope of protection of the present application. Therefore, any equivalent changes made based on the structure, shape, and principle of the present application should be included in the scope of protection of the present application.

Claims

1. A method for preparing 5-aminolevulinic acid methyl ester hydrochloride, characterized in that: The following steps are involved: Step S101: adding methanol to a reaction vessel, cooling the temperature to 0-10° C., adding thionyl chloride dropwise under temperature control, and stirring the mixture to obtain a reaction solution after the addition is complete. The mixture is then subjected to reduced pressure distillation to control the pH value of the reaction solution to 1.5-2.5; Step S102: adding 5-aminolevulinic acid hydrochloride to the reaction solution of step S101, heating to 60-65° C. after the addition is complete, and performing reflux stirring; Step S103: adding a crystallization accelerator to the system of step S102, stirring and crystallizing after the addition is completed, filtering, and drying to obtain 5-aminolevulinic acid methyl ester hydrochloride.

2. The preparation method of 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, wherein The temperature of the reduced pressure distillation treatment is 30-40° C., and the vacuum degree is 0.08-0.09 MPa.

3. The preparation method of 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, wherein The crystallization accelerator is methyl tert-butyl ether, tetrahydrofuran or methyltetrahydrofuran.

4. The preparation method of 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, wherein The crystallization temperature in step S103 is 0-30°C.

5. The preparation method of 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, wherein Add 5-11 ml of crystallization accelerator to every 1 g of 5-aminolevulinic acid hydrochloride.

6. The preparation method of 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, characterized in that, The mass ratio of the 5-aminolevulinic acid hydrochloride to the thionyl chloride is 1:0.9-1.

7. The method for preparing 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, wherein Use 2-3 ml of methanol for every 1 g of 5-aminolevulinic acid hydrochloride.

8. The method for preparing 5-aminolevulinic acid methyl ester hydrochloride according to claim 1, wherein The method further includes the step of purifying the 5-aminolevulinic acid methyl ester hydrochloride, which is specifically as follows: Step S104: dissolving the methyl 5-aminolevulinate hydrochloride obtained in step S103 in methanol, and then adding acetone dropwise thereto. After the addition is complete, the internal temperature is cooled to 0-10° C., stirred for crystallization, and then filtered. The filter cake is rinsed with acetone, and finally the filter cake is vacuum dried to obtain the product.

9. The method for preparing 5-aminolevulinic acid methyl ester hydrochloride according to claim 8, wherein The vacuum drying process in step S104 is performed at a temperature of 50-60° C. and a vacuum degree of ≤-0.09 MPa.

10. 5-aminolevulinic acid methyl ester hydrochloride obtained by the preparation method according to any one of claims 1 to 9.

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