Method for preparing 5-aminolevulinic acid hydrochloride

Abstract

The present application relates to the technical field of drug preparation. Disclosed is a method for preparing 5-aminolevulinic acid hydrochloride. In the method for preparing 5-aminolevulinic acid hydrochloride provided by the present application, monomethyl succinate and thionyl chloride are used as starting materials, which effectively solves the problem of the high contents of by-products and impurities caused by the poor stability of methyl 4-chloro-4-oxobutanoate when used as a starting material. Specifically, by overcoming the defect of the poor stability of methyl 4-chloro-4-oxobutanoate, the method effectively avoids the formation of degradation impurities derived from methyl 4-chloro-4-oxobutanoate, such as succinic acid, monomethyl succinate and dimethyl succinate, thereby effectively avoiding the formation of by-products in subsequent reaction processes.

Description

A method for preparing 5-aminolevulinic acid salt Technical Field

[0001] This application belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing 5-aminolevulinic acid salt. Background Technology

[0002] 5-Aminolevulinic acid (5-ALA) is a prodrug that metabolizes intracellularly to form the fluorescent molecule protoporphyrin (PPIX). Exogenous application of 5-ALA leads to highly selective accumulation of PPIX in tumor cells and epithelial tissues. Upon excitation with blue light (λ=400-410nm), PPIX selectively accumulated in malignant tissues emits reddish-purple light. Therefore, 5-ALA is often used clinically as a photosensitizing diagnostic drug.

[0003] Photodynamic therapy (ALA-PDT) is a novel technique that combines 5-ALA and a corresponding light source to selectively destroy diseased tissue through photodynamic reactions. Its main mechanism of action is based on the interaction of light, photosensitizers, and oxygen, making it a new treatment method for diseases.

[0004] Although the structure of 5-aminoketovalerate is simple, its synthesis is quite difficult. In the process of realizing this application, the inventors found that the existing synthetic routes for 5-aminoketovalerate have problems such as low synthesis yield, high impurity content, high production cost, and difficulty in achieving industrial production. Summary of the Invention

[0005] The purpose of this application is to provide a method for preparing 5-aminoketovalerate salt, in order to solve the problems of low synthesis yield, high impurity content, high production cost, and difficulty in industrial production of existing synthetic routes for 5-aminoketovalerate salt.

[0006] To achieve the above-mentioned objectives, the technical solution adopted in this application is as follows:

[0007] This application provides a method for preparing 5-aminolevulinic acid salt, comprising the following steps:

[0008] S1. Chloride monomethyl succinate and thionyl chloride to obtain monomethyl succinate acyl chloride;

[0009] S2. The succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain methyl 4-oxo-4-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)butyrate (C 14 H 13 NO5);

[0010] S3, make C obtained in step S2 14H 13 NO5 undergoes a hydrolysis reaction.

[0011] In one optional implementation, the time interval between step S1 and step S2 shall not exceed 10 hours.

[0012] In an optional embodiment, in step S2, the succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain C. 14 H 13 During the NO5 process, the operating temperature is controlled between 0 and 20°C.

[0013] In an optional embodiment, in step S2, the succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain C. 14 H 13 NO5, including:

[0014] Hippuric acid, 4-methylpyridine, and succinic acid monomethyl ester chloride obtained in step S1 were added to a reaction vessel and stirred at 0–20°C until the reaction was complete. The mixture was then cooled and hydrochloric acid was added dropwise to adjust the pH to 1–2. The precipitated solid was separated, dried, and then slurried with ethyl acetate. After crystallization and decolorization, C was obtained. 14 H 13 NO5.

[0015] In one alternative embodiment, the ratio of hippuric acid, 4-methylpyridine, and monomethyl succinate chloride by weight is (0.8–1.2):(3.0–6.0):(2.0–4.0).

[0016] In an optional embodiment, in step S2, the succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain C. 14 H 13 NO5, including:

[0017] S201. Take the hippuric acid and 4-methylpyridine and add them to the reaction vessel. Control the temperature to 0-20℃. Add the succinic acid monomethyl ester chloride obtained in step S1 dropwise and stir until the reaction is completed to obtain the reaction mother liquor.

[0018] S202. At 0-20℃, the reaction mother liquor is added dropwise to water, hydrochloric acid is added to adjust the pH to 1-2, the precipitated solid is separated and washed to obtain the crude first intermediate product;

[0019] S203. The first crude intermediate and ethyl acetate are added to a reaction vessel, and the temperature is controlled at 0-20°C. After stirring, solid-liquid separation, washing and drying, the second crude intermediate is obtained.

[0020] S204. The crude intermediate is subjected to crystallization and decolorization at 0-20°C to obtain C. 14 H 13 NO5.

[0021] Specifically, the crude second intermediate is subjected to crystallization and decolorization at 0–20°C to obtain C. 14 H 13 NO5, including:

[0022] N,N-dimethylacetamide and the crude second intermediate were added to a reaction vessel, and the temperature was maintained at 10±10℃ with stirring. Activated carbon was added, and stirring was continued with stirring. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the centrifuged solid and ethyl acetate were added to the reaction vessel, and the temperature was maintained at 10±10℃ with stirring. After centrifugation, the filter cake was washed with ethyl acetate to obtain C. 14 H 13 NO5.

[0023] In an optional embodiment, in step S1, methyl succinate and thionyl chloride are subjected to a chlorination reaction to obtain methyl succinate acyl chloride, comprising:

[0024] Monomethyl succinate, thionyl chloride, toluene, and a catalyst were added to a reaction vessel and reacted completely at 65–85°C. The toluene and excess thionyl chloride were then concentrated to remove the residue, yielding monomethyl succinate acyl chloride.

[0025] In one alternative embodiment, the catalyst comprises at least one selected from N,N-dimethylformamide, N-methylpyrrolidone, 2,6-diisopropylaniline, and N,N-diisopropylethylamine.

[0026] And / or, by weight, the ratio of monomethyl succinate, thionyl chloride, toluene and catalyst is (600-1200): (800-1400): (1800-3000): (0.8-1.2).

[0027] For example, in step S1, the chlorination reaction of monomethyl succinate and thionyl chloride to obtain monomethyl succinate acyl chloride may include:

[0028] S101. Add monomethyl succinate, toluene and catalyst to the reaction vessel, and heat to 45-65℃ to obtain a mixture.

[0029] S102. Add thionyl chloride to the mixture obtained in step S101, heat to 65-85°C, keep warm and stir until the reaction is complete, and obtain the chlorinated product.

[0030] S103. Remove toluene and excess thionyl chloride from the chlorinated product to obtain monomethyl succinate chloride.

[0031] In an alternative implementation, in step S3, the C obtained in step S2 is... 14 H 13 NO5 undergoes hydrolysis reactions, including:

[0032] C 14 H 13 NO5 is hydrolyzed under strong acid and high temperature conditions. The hydrolysis product is filtered, the liquid is extracted and concentrated, the resulting solid product is reconstituted with water, acetone is added dropwise, the precipitated solid is separated, washed and dried.

[0033] The dried product was crystallized in dilute hydrochloric acid to give 5-aminoketovalerate.

[0034] For example, in step S3, the C obtained in step S2 is made... 14 H 13 The hydrolysis of NO5 can include:

[0035] S301, make C 14 H 13 NO5 is contacted with hydrochloric acid solution, heated to 60-80℃, and stirred until hydrolysis is complete to obtain the hydrolysis product.

[0036] S302. The hydrolysis product is cooled to room temperature, filtered under pressure, the filter cake is washed with deionized water, the filtrate and washing liquid are combined, extracted, and the resulting aqueous phase is concentrated to obtain the first solid product.

[0037] S303. The first solid product is re-dissolved in water, activated carbon is added and stirred, filtered under pressure, the filter cake is washed with acetone and dried to obtain the second solid product.

[0038] S304. Add the second solid product to the hydrochloric acid solution, add activated carbon and stir, filter under pressure, wash the filter cake with deionized water and acetone, keep the temperature at 20±10℃ and stir, centrifuge, wash the filter cake with acetone, collect the solid and dry it under vacuum at 20±5℃ to obtain aminolevulinic acid hydrochloride.

[0039] In an optional embodiment, the preparation method further includes the step of preparing the hippuric acid:

[0040] Glycine and benzoyl chloride were reacted in sodium hydroxide solution. After the reaction was completed, the temperature was lowered and hydrochloric acid was added dropwise to adjust the pH to 2-3. The precipitated solid was separated, and the wet filter cake was slurried with hot water to remove the impurity benzoic acid, thus obtaining hippuric acid.

[0041] Optionally, the ratio of glycine to benzoyl chloride, by weight, is (0.8–1.2):(0.96–1.44).

[0042] Based on the above technical solution, this application has at least the following beneficial effects:

[0043] (1) The preparation method of 5-aminoketovalerate salt provided in this application uses monomethyl succinate and thionyl chloride as starting materials, which effectively solves the problem of high content of by-products and impurities caused by the poor stability of monomethyl succinate chloride as the starting material. Specifically, by overcoming the problem of poor stability of monomethyl succinate chloride, the generation of degradation impurities such as succinic acid, monomethyl succinate, and dimethyl succinate of monomethyl succinate chloride is effectively avoided, thereby effectively avoiding the generation of by-products in subsequent reaction processes.

[0044] (2) The preparation method of 5-aminoketovalerate salt provided in this application optimizes the process parameters of the coupling reaction between succinic acid monomethyl ester chloride and hippuric acid, controls the operating temperature to 0-20℃, significantly reduces the generation of impurities and by-products in the coupling reaction, and significantly improves the intermediate product C 14 H 13 The yield and purity of NO5 can be improved, thereby significantly increasing the yield and purity of the finished product.

[0045] (3) The preparation method of 5-aminoketovalerate salt provided in this application involves classical and traditional reactions, with readily available raw materials, low cost, and easy industrial production. Detailed Implementation

[0046] To further illustrate the technical means and results adopted by this application to achieve the intended inventive purpose, the following preferred embodiments are used to describe in detail the specific implementation methods, technical solutions, and features according to this application. Specific features, structures, or characteristics in the various embodiments described below can be combined in any suitable form.

[0047] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0048] The synthetic route for 5-aminolevulinic acid salt provided in this invention is as follows:

[0049]

[0050] Among them, GLL01 is intermediate 01, hippuric acid; GLL02 is intermediate 02, succinic acid monomethyl ester chloride; GLL03 is intermediate 03, methyl 4-oxo-4-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)butyrate; and GLL04 is intermediate 04, crude aminolevulinic acid hydrochloride. Step 1 is the amidation reaction, step 2 is the chlorination reaction, step 3 is the coupling reaction, step 4 is the hydrolysis reaction, and step 5 is the purification step.

[0051] The present application will be further described in detail below with reference to specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in this application. Example 1

[0052] 5-Aminolevulinate salt was prepared according to the following method:

[0053] (1) Preparation of intermediate 01:

[0054] Add 600 mL of 10% sodium hydroxide solution to a reaction vessel, maintain the temperature at 20 °C, add approximately 60 g of glycine, stir until homogeneous, then add approximately 72 g of benzoyl chloride, and stir at 20 °C until the reaction is complete. Add approximately 86.0 g of hydrochloric acid dropwise to the vessel to adjust the pH to 2.5, maintain the temperature at 5 °C, stir, and precipitate a solid. Centrifuge and collect the solid. Add approximately 930.0 g of deionized water and the centrifuged solid to the reaction vessel, maintain the temperature at 70 °C, stir, and precipitate until the reaction is complete. Cool to 20 °C, centrifuge, and wash the filter cake with deionized water and ethyl acetate, respectively, to obtain intermediate 01 (hippuric acid). The purity of intermediate 01 is 99.0%, and the yield is 90.5%.

[0055] (2) Preparation of intermediate O2:

[0056] Approximately 200.0 g of monomethyl succinate, approximately 0.20 g of N,N-dimethylformamide, and approximately 400.0 g of toluene were added to a reaction vessel, and the temperature was raised to 55 °C. Approximately 278.0 g of thionyl chloride was added, and the temperature was raised to 75 °C. The mixture was kept at this temperature and stirred until the reaction was complete. The solvent was removed under reduced pressure, and toluene was added to continue the solvent removal under reduced pressure until no fraction was obtained. The resulting intermediate O2 (monomethyl succinate acyl chloride) was reserved for later use.

[0057] (3) Preparation of intermediate 03:

[0058] Within 10 hours after the completion of step (2), take approximately 120 g of intermediate 01 and approximately 415.0 g of 4-methylpyridine obtained in step (1) and add them to the reaction vessel. Cool the vessel to 10 °C and add approximately 260 g of intermediate 02 obtained in step (2) dropwise. Stir until the reaction is complete to obtain the reaction mother liquor. Add deionized water to another reaction vessel and add the reaction mother liquor dropwise at 10 °C. Continue to slowly add hydrochloric acid until the pH value is 1.5. Centrifuge and wash the filter cake with deionized water to obtain the crude product.

[0059] The crude product and about 500.0 g of ethyl acetate were added to a reaction vessel, the temperature was controlled at 10 °C, the mixture was stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain the dried product.

[0060] Approximately 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction vessel. The temperature was controlled at 10 °C, and the mixture was stirred while maintaining the temperature. Approximately 10 g of activated carbon was added, and the mixture was stirred while maintaining the temperature. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the filter cake was washed again with deionized water. The solid obtained after washing was added to the reaction vessel together with ethyl acetate. The temperature was controlled at 10 °C, and the mixture was stirred and centrifuged. The filter cake was washed with ethyl acetate to obtain intermediate O3 (C 14 H 13 NO5).

[0061] (4) Preparation of intermediate O4:

[0062] Add approximately 267.0 g of hydrochloric acid and approximately 55.0 g of deionized water to the reaction vessel, stir evenly, add dropwise the hydrochloric acid solution of intermediate O3 prepared in step (3), control the temperature at 70 ℃, keep warm and stir until the reaction is complete, cool to room temperature, filter under pressure, and wash with deionized water; take the filtrate, and continue to extract twice with dichloromethane (approximately 250 g each time), and concentrate the aqueous phase obtained from the extraction under reduced pressure at 75 ℃ until no fraction remains;

[0063] After the vacuum concentration was completed, deionized water was added to dissolve and clarify the solution. Activated carbon was then added, the mixture was stirred at room temperature, filtered under pressure, washed with acetone, and the solutions were combined. The solid was collected and dried under vacuum at 25 °C to obtain intermediate 04 (crude 5-aminoketovalerate).

[0064] (5) Product refining:

[0065] Take about 10.0 g of hydrochloric acid and about 24.5 g of deionized water and add them to the reaction vessel. After stirring evenly, add the intermediate O4 prepared in step (4) and keep it at 20 °C for reaction. Add about 1.0 g of activated carbon and stir at 20 °C. Filter under pressure and wash with deionized water and acetone. Keep the temperature at 20 °C and stir. Centrifuge and wash the filter cake with acetone. Collect the solid and dry it under vacuum at 20 °C to obtain 5-aminoketovalerate salt. Example 2

[0066] The 5-aminolevulinic acid salt was prepared according to the method of Example 1, except that in step (3) of this example, the temperature of each operation was controlled at 0 °C when preparing intermediate O3. Specifically, step (3) of this example is as follows:

[0067] Within 10 hours after the completion of step (2), take approximately 120 g of intermediate 01 and approximately 415.0 g of 4-methylpyridine obtained in step (1) and add them to the reaction vessel. Cool the vessel to 0 °C and add approximately 260 g of intermediate 02 obtained in step (2) dropwise. Stir until the reaction is complete to obtain the reaction mother liquor. Add deionized water to another reaction vessel and add the reaction mother liquor dropwise at 0 °C. Continue to slowly add hydrochloric acid until the pH value is 1.5. Centrifuge and wash the filter cake with deionized water to obtain the crude product.

[0068] The crude product and about 500.0 g of ethyl acetate were added to a reaction vessel, the temperature was controlled at 0 °C, the mixture was stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain the dried product.

[0069] Approximately 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction vessel. The temperature was maintained at 0 °C, and the mixture was stirred while keeping it warm. Approximately 10 g of activated carbon was added, and the mixture was stirred while keeping it warm again. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the filter cake was washed again with deionized water. The solid obtained after washing was added to the reaction vessel together with ethyl acetate. The temperature was maintained at 0 °C, and the mixture was stirred and centrifuged. The filter cake was washed with ethyl acetate to obtain intermediate O3 (C 14 H 13 NO5). Example 3

[0070] The 5-aminolevulinic acid salt was prepared according to the method of Example 1, except that in step (3) of this example, the temperature of each operation was controlled at 20 °C when preparing intermediate O3. Specifically, step (3) of this example is as follows:

[0071] Within 10 hours after the completion of step (2), take approximately 120 g of intermediate 01 and approximately 415.0 g of 4-methylpyridine obtained in step (1) and add them to the reaction vessel. Cool the vessel to 20 °C and add approximately 260 g of intermediate 02 obtained in step (2) dropwise. Stir until the reaction is complete to obtain the reaction mother liquor. Add deionized water to another reaction vessel and add the reaction mother liquor dropwise at 20 °C. Continue to slowly add hydrochloric acid until the pH value is 1.5. Centrifuge and wash the filter cake with deionized water to obtain the crude product.

[0072] The crude product and about 500.0 g of ethyl acetate were added to a reaction vessel, the temperature was controlled at 20 °C, the mixture was stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain the dried product.

[0073] Approximately 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction vessel. The temperature was controlled at 20 °C, and the mixture was stirred while maintaining the temperature. Approximately 10 g of activated carbon was added, and the mixture was stirred while maintaining the temperature. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the filter cake was washed again with deionized water. The solid obtained after washing was added to the reaction vessel together with ethyl acetate. The temperature was controlled at 20 °C, and the mixture was stirred and centrifuged. The filter cake was washed with ethyl acetate to obtain intermediate O3 (C 14 H 13 NO5). Example 4

[0074] The 5-aminolevulinic acid salt was prepared according to the method of Example 1, except that in step (3) of this example, the temperature of each operation was controlled at room temperature (25 ℃) when preparing intermediate O3. Specifically, step (3) of this example is as follows:

[0075] Within 10 hours after the completion of step (2), take approximately 120 g of intermediate 01 and approximately 415.0 g of 4-methylpyridine obtained in step (1) and add them to the reaction vessel. Add approximately 260 g of intermediate 02 obtained in step (2) dropwise at room temperature (25 ℃) and stir until the reaction is complete to obtain the reaction mother liquor. Add deionized water to another reaction vessel and add the reaction mother liquor dropwise at room temperature (25 ℃). Continue to slowly add hydrochloric acid until the pH value is 1.5. Centrifuge and wash the filter cake with deionized water to obtain the crude product.

[0076] The crude product and about 500.0 g of ethyl acetate were added to a reaction vessel, stirred at room temperature (25 °C), centrifuged, and the filter cake was washed with about 240.0 g of ethyl acetate. The product was then dried under reduced pressure to obtain the dried product.

[0077] Approximately 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction vessel and stirred at room temperature (25 °C). Approximately 10 g of activated carbon was added, and stirring and stirring continued. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the filter cake was washed again with deionized water. The solid residue after washing was added to the reaction vessel along with ethyl acetate, stirred at room temperature (25 °C), centrifuged, and the filter cake was washed with ethyl acetate to obtain intermediate O3 (C). 14 H 13 NO5).

[0078] Comparative Example 1

[0079] 5-Aminolevulinate salt was prepared according to the following method:

[0080] (1) Take 120.0 g hippuric acid and about 415.0 g 4-methylpyridine and add them to the reaction vessel. Cool the temperature to 10 °C and add 260 g succinic acid monomethyl ester chloride dropwise. Stir until the reaction is complete to obtain the reaction mother liquor. Add deionized water to another reaction vessel and add the reaction mother liquor dropwise at 10 °C. Continue to slowly add hydrochloric acid until the pH value is 1.5. Centrifuge and wash the filter cake with deionized water to obtain the crude product.

[0081] The crude product and about 500.0 g of ethyl acetate were added to a reaction vessel, the temperature was controlled at 10 °C, the mixture was stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain the dried product.

[0082] Approximately 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction vessel. The temperature was maintained at 10 °C, and the mixture was stirred while keeping it warm. Approximately 10 g of activated carbon was added, and the mixture was stirred while keeping it warm again. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the filter cake was washed again with deionized water. The solid obtained after washing was added to the reaction vessel together with ethyl acetate. The temperature was maintained at 10 °C, and the mixture was stirred and centrifuged. The filter cake was washed with ethyl acetate to obtain intermediate C. 14 H 13 NO5.

[0083] (2) Add approximately 267.0 g of hydrochloric acid and approximately 55.0 g of deionized water to the reaction vessel, stir until homogeneous, and add dropwise the intermediate C prepared in step (2). 14 H 13 The hydrochloric acid solution of NO5 was prepared at a temperature of 70 °C and stirred until the reaction was complete. The solution was then cooled to room temperature, filtered under pressure, and washed with deionized water. The filtrate was then extracted twice more with dichloromethane (approximately 250 g each time). The aqueous phase obtained from the extraction was concentrated under reduced pressure at 75 °C until no fraction remained.

[0084] After vacuum concentration, deionized water was added to dissolve and clarify the solution. Activated carbon was then added, the mixture was stirred at room temperature, filtered under pressure, washed with acetone, and the solutions were combined. The solid was collected and dried under vacuum at 25 °C to obtain crude 5-aminoketolate salt.

[0085] (3) Take about 10.0 g of hydrochloric acid and about 24.5 g of deionized water and add them to the reaction vessel. After stirring evenly, add the crude 5-aminoketovalerate salt obtained in step (4) and keep it at 20 °C. Add about 1.0 g of activated carbon and stir at 20 °C. Filter under pressure and wash with deionized water and acetone. Keep the temperature at 20 °C and stir. Centrifuge and wash the filter cake with acetone. Collect the solid and dry it under vacuum at 20 °C to obtain 5-aminoketovalerate salt.

[0086] Comparative Example 2

[0087] 5-Aminolevulinate salt was prepared according to the following method:

[0088] (1) Take 120g hippuric acid and about 415.0g 4-methylpyridine and add them to the reaction vessel. Add 260g succinic acid monomethyl ester chloride dropwise at room temperature (25 ℃) and stir until the reaction is complete to obtain the reaction mother liquor. Add deionized water to another reaction vessel and add the reaction mother liquor dropwise at room temperature (25 ℃). Continue to slowly add hydrochloric acid until the pH value is 1.5. Centrifuge and wash the filter cake with deionized water to obtain the crude product.

[0089] The crude product and about 500.0 g of ethyl acetate were added to a reaction vessel, stirred at room temperature (25 °C), centrifuged, and the filter cake was washed with about 240.0 g of ethyl acetate. The product was then dried under reduced pressure to obtain the dried product.

[0090] Approximately 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction vessel and stirred at room temperature (25 °C). Approximately 10 g of activated carbon was added, and stirring and stirring continued. The mixture was then filtered under pressure, and the filter cake was washed with deionized water. After centrifugation, the filter cake was washed again with deionized water. The solid obtained after washing was added to the reaction vessel along with ethyl acetate, stirred at room temperature (25 °C), centrifuged, and the filter cake was washed with ethyl acetate to obtain intermediate C. 14 H 13 NO5.

[0091] (2) Add approximately 267.0 g of hydrochloric acid and approximately 55.0 g of deionized water to the reaction vessel, stir until homogeneous, and add dropwise the intermediate C prepared in step (2). 14 H 13The hydrochloric acid solution of NO5 was prepared at a temperature of 70 °C and stirred until the reaction was complete. The solution was then cooled to room temperature, filtered under pressure, and washed with deionized water. The filtrate was then extracted twice more with dichloromethane (approximately 250 g each time). The aqueous phase obtained from the extraction was concentrated under reduced pressure at 75 °C until no fraction remained.

[0092] After vacuum concentration, deionized water was added to dissolve and clarify the solution. Activated carbon was then added, the mixture was stirred at room temperature, filtered under pressure, washed with acetone, and the solutions were combined. The solid was collected and dried under vacuum at 25 °C to obtain crude 5-aminoketolate salt.

[0093] (3) Take about 10.0 g of hydrochloric acid and about 24.5 g of deionized water and add them to the reaction vessel. After stirring evenly, add the crude 5-aminoketovalerate salt obtained in step (4) and keep it at 20 °C. Add about 1.0 g of activated carbon and stir at 20 °C. Filter under pressure and wash with deionized water and acetone. Keep the temperature at 20 °C and stir. Centrifuge and wash the filter cake with acetone. Collect the solid and dry it under vacuum at 20 °C to obtain 5-aminoketovalerate salt.

[0094] Experimental Example 1

[0095] Intermediate C in Examples 1-4 and Comparative Examples 1-2 were tested respectively. 14 H 13 The purity and yield of NO5 are shown in Table 1.

[0096] Table 1. Intermediate C in Examples 1-4 and Comparative Examples 1-2 14 H 13 Purity and yield of NO5

[0097]

[0098] Note: Purity limit: ≥97.0%;

[0099] RRT 0.74 (relative retention time 0.74) Impurity limit: ≤2.0%;

[0100] Other impurities limit: ≤1.0%;

[0101] Yield calculation: .

[0102] Experiment Example 2

[0103] The purity and yield of the 5-aminolevulinic acid salts finally prepared in Examples 1-4 and Comparative Examples 1-2 were tested respectively, and the test results are shown in Table 2.

[0104] Table 2 Purity and yield of 5-aminolevulinic acid salt in Examples 1-4 and Comparative Examples 1-2

[0105]

[0106] Yield calculation: .

[0107] The above description is merely a preferred embodiment of this application; however, the scope of protection of this application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in this application, based on the technical solution and its improved concept, should be covered within the scope of protection of this application.

Claims

1. A method for preparing 5-aminolevulinic acid salt, characterized in that, Includes the following steps: S1. Chloride monomethyl succinate and thionyl chloride to obtain monomethyl succinate acyl chloride; S2. The succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain methyl 4-oxo-4-(5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)butyrate (C 14 H 13 NO5); S3, make C obtained in step S2 14 H 13 NO5 undergoes a hydrolysis reaction.

2. The preparation method according to claim 1, characterized in that, The time interval between step S1 and step S2 shall not exceed 10 hours.

3. The preparation method according to claim 1, characterized in that, In step S2, the succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain C. 14 H 13 During the NO5 process, the operating temperature is controlled between 0 and 20°C.

4. The preparation method according to claim 3, characterized in that, In step S2, the succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain C. 14 H 13 NO5, including: Hippuric acid, 4-methylpyridine, and succinic acid monomethyl ester chloride obtained in step S1 were added to a reaction vessel and stirred at 0–20°C until the reaction was complete. The mixture was then cooled and hydrochloric acid was added dropwise to adjust the pH to 1–2. The precipitated solid was separated, dried, and then slurried with ethyl acetate. After crystallization and decolorization, C was obtained. 14 H 13 NO5.

5. The preparation method according to claim 4, characterized in that, The ratio of hippuric acid, 4-methylpyridine and succinic acid monomethyl ester chloride by weight is (0.8-1.2):(3.0-6.0):(2.0-4.0).

6. The preparation method according to claim 4, characterized in that, In step S2, the succinic acid monomethyl ester chloride obtained in step S1 is coupled with hippuric acid to obtain C. 14 H 13 NO5, including: S201. Take the hippuric acid and 4-methylpyridine and add them to the reaction vessel. Control the temperature to 0-20℃. Add the succinic acid monomethyl ester chloride obtained in step S1 dropwise and stir until the reaction is completed to obtain the reaction mother liquor. S202. At 0-20℃, the reaction mother liquor is added dropwise to water, hydrochloric acid is added to adjust the pH to 1-2, the precipitated solid is separated and washed to obtain the crude first intermediate product; S203. The first crude intermediate and ethyl acetate are added to a reaction vessel, and the temperature is controlled at 0-20°C. After stirring, solid-liquid separation, washing and drying, the second crude intermediate is obtained. S204. The crude intermediate is subjected to crystallization and decolorization at 0-20°C to obtain C. 14 H 13 NO5.

7. The preparation method according to claim 1, characterized in that, In step S1, monomethyl succinate and thionyl chloride are subjected to a chlorination reaction to obtain monomethyl succinate acyl chloride, comprising: Monomethyl succinate, thionyl chloride, toluene, and a catalyst were added to a reaction vessel and reacted completely at 65–85°C. The toluene and excess thionyl chloride were then concentrated to remove the residue, yielding monomethyl succinate acyl chloride.

8. The preparation method according to claim 7, characterized in that, The catalyst comprises at least one of N,N-dimethylformamide, N-methylpyrrolidone, 2,6-diisopropylaniline and N,N-diisopropylethylamine; And / or, by weight, the ratio of monomethyl succinate, thionyl chloride, toluene and catalyst is (600-1200): (800-1400): (1800-3000): (0.8-1.2).

9. The preparation method according to claim 1, characterized in that, In step S3, the C obtained in step S2 is made... 14 H 13 NO5 undergoes hydrolysis reactions, including: C 14 H 13 NO5 is hydrolyzed under strong acid and high temperature conditions. The hydrolysis product is filtered, the liquid is extracted and concentrated, the resulting solid product is reconstituted with water, acetone is added dropwise, the precipitated solid is separated, washed and dried. The dried product was crystallized in dilute hydrochloric acid to give 5-aminoketovalerate.

10. The preparation method according to claim 1, characterized in that, The preparation method further includes the step of preparing hippuric acid: Glycine and benzoyl chloride were reacted in sodium hydroxide solution. After the reaction was completed, the temperature was lowered and hydrochloric acid was added dropwise to adjust the pH to 2-3. The precipitated solid was separated, and the wet filter cake was slurried with hot water to remove the impurity benzoic acid, thus obtaining hippuric acid. Optionally, the ratio of glycine to benzoyl chloride, by weight, is (0.8–1.2):(0.96–1.44).

Images