Preparation method of 5-aminolevulinic acid hydrochloride

Abstract

The invention relates to the technical field of medicine preparation, and discloses a preparation method of 5-aminolevulinic acid hydrochloride. According to the preparation method of the 5-aminolevulinic acid hydrochloride, provided by the invention, the monomethyl succinate and the thionyl chloride are used as starting materials, so that the problems of high content of byproducts and impurities caused by poor stability of monomethyl succinate acyl chloride when the monomethyl succinate acyl chloride is used as the starting material are effectively solved. Specifically, due to the fact that the problem of poor stability of the succinic acid monomethyl ester acyl chloride is solved, generation of succinic acid, succinic acid monomethyl ester, dimethyl succinate and the like which are degradation impurities of the succinic acid monomethyl ester acyl chloride is effectively avoided, and then generation of by-products in the subsequent reaction process can be effectively avoided.

Description

Technical Field

[0001] The present application belongs to the technical field of drug preparation, and specifically relates to a method for preparing 5-aminolevulinic acid hydrochloride. Background Art

[0002] 5-aminolevulinic acid (5-ALA) is a prodrug that can be metabolized intracellularly to form the fluorescent molecule protoporphyrin (PPIX). Exogenous application of 5-ALA can lead to highly selective accumulation of PPIX in tumor cells and epithelial tissues. After excitation with blue light (λ = 400-410nm), PPIX selectively accumulated in malignant tissues will emit red-purple light. Therefore, 5-ALA is often used as a photosensitizing diagnostic drug in clinical practice.

[0003] "Photodynamic therapy" (ALA-PDT) is a new technology that combines 5-ALA and corresponding light sources to selectively destroy diseased tissues through photodynamic reactions. Its main mechanism of action is a new disease treatment method based on the interaction between light, photosensitizers and oxygen.

[0004] Although the structure of 5-aminolevulinic acid hydrochloride is simple, its synthesis is quite difficult. In the process of realizing the present application, the inventors found that the existing synthesis route of 5-aminolevulinic acid hydrochloride has the problems of low synthesis yield, high impurity content, high production cost, and difficulty in industrial production. Summary of the invention

[0005] The purpose of the present application is to provide a method for preparing 5-aminolevulinic acid hydrochloride to solve the problems of low synthesis yield, high impurity content, high production cost, and difficulty in industrial production in the existing synthesis route of 5-aminolevulinic acid hydrochloride.

[0006] In order to achieve the above invention purpose, the technical solution adopted in this application is:

[0007] The present application provides a method for preparing 5-aminolevulinic acid hydrochloride, comprising the following steps:

[0008] S1, subjecting monomethyl succinate and thionyl chloride to a chlorination reaction to obtain monomethyl succinate chloride;

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

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

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

[0012] In an optional embodiment, in step S2, the succinic acid monomethyl 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 at 0-20°C.

[0013] In an optional embodiment, in step S2, the succinic acid monomethyl 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 chloride obtained in step S1 are added to a reaction kettle, stirred at 0-20°C until the reaction is completed, cooled and hydrochloric acid is added dropwise to adjust the pH to 1-2, the precipitated solid is separated, dried, pulped with ethyl acetate, and then crystallized and decolorized to obtain C 14 H 13 NO5.

[0015] In an optional embodiment, the ratio of hippuric acid, 4-methylpyridine and succinic acid monomethyl chloride is (0.8-1.2): (3.0-6.0): (2.0-4.0) in parts by weight.

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

[0017] S201, adding the hippuric acid and 4-methylpyridine into a reaction kettle, controlling the temperature to 0-20° C., dropwise adding the succinic acid monomethyl chloride obtained in step S1, and stirring until the reaction is completed to obtain a reaction mother liquor;

[0018] S202, dropping the reaction mother liquid into water at 0-20° C., adding hydrochloric acid to adjust the pH to 1-2, separating and washing the precipitated solid to obtain a crude first intermediate;

[0019] S203, adding the first intermediate crude product and ethyl acetate into a reaction kettle, controlling the temperature to 0-20° C., stirring, solid-liquid separation, washing, and drying to obtain a second intermediate crude product;

[0020] S204, crystallizing and decolorizing the second intermediate crude product at 0-20°C to obtain C 14 H13 NO5.

[0021] Specifically, the second intermediate crude product is crystallized and decolorized at 0-20°C to obtain C 14 H 13 NO5, including:

[0022] Add N,N-dimethylacetamide and the second intermediate crude product to the reactor, control the temperature to 10±10℃, keep warm and stir, add activated carbon, continue to keep warm and stir, filter press, wash the filter cake with deionized water, centrifuge, add the centrifuged solid and ethyl acetate to the reactor, control the temperature to 10±10℃, stir, centrifuge, wash the filter cake with ethyl acetate, and obtain C 14 H 13 NO5.

[0023] In an optional embodiment, in step S1, succinic acid monomethyl ester and thionyl chloride are subjected to a chlorination reaction to obtain succinic acid monomethyl ester chloride, comprising:

[0024] Monomethyl succinate, thionyl chloride, toluene and a catalyst are added into a reaction kettle, reacted completely at 65-85° C., and concentrated to remove toluene and excess thionyl chloride to obtain monomethyl succinate chloride.

[0025] In an optional embodiment, the catalyst includes at least one of N,N-dimethylformamide, N-methylpyrrolidone, 2,6-diisopropylaniline and N,N-diisopropylethylamine;

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

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

[0028] S101, adding monomethyl succinate, toluene and a catalyst into a reaction kettle, heating the kettle to 45-65° C., and obtaining a mixed material;

[0029] S102, adding thionyl chloride to the mixture obtained in step S101, heating to 65-85° C., and stirring at the same temperature until the reaction is complete to obtain a chlorinated product;

[0030] S103, removing toluene and excess thionyl chloride in the chlorinated product to obtain succinic acid monomethyl chloride.

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

[0032] C 14 H 13 NO5 is hydrolyzed under strong acid and high temperature conditions, the hydrolyzate is filtered, the liquid is extracted and concentrated, the solid product is re-dissolved in water and 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-aminolevulinic acid hydrochloride.

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

[0035] S301, Make C 14 H 13 NO5 is contacted with hydrochloric acid solution, heated to 60-80°C, and stirred at this temperature until hydrolysis is complete to obtain a hydrolysis product;

[0036] S302, cooling the hydrolyzate to room temperature, filtering, washing the filter cake with deionized water, combining the filtrate and the washing liquid, extracting, concentrating the obtained aqueous phase, and obtaining a first solid product;

[0037] S303, re-dissolving the first solid product with water, adding activated carbon and stirring, filtering, washing the filter cake with acetone, and drying to obtain a second solid product;

[0038] S304, adding the second solid product to a hydrochloric acid solution, adding activated carbon and stirring, filtering, washing the filter cake with deionized water and acetone, controlling the temperature to 20±10°C and stirring, centrifuging, washing the filter cake with acetone, collecting the solid and drying it in vacuo at 20±5°C to obtain aminolevulinic acid hydrochloride.

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

[0040] glycine and benzoyl chloride are reacted in a sodium hydroxide solution, after the reaction is completed, the temperature is lowered and hydrochloric acid is added dropwise to adjust the pH value to 2-3, the precipitated solid is separated, and the wet filter cake is pulped with hot water to remove the impurity benzoic acid to obtain the hippuric acid;

[0041] Optionally, in parts by weight, the ratio of glycine to benzoyl chloride 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-aminolevulinic acid hydrochloride provided in the present application uses monomethyl succinate and thionyl chloride as starting materials, which effectively solves the problem of high by-product and impurity content caused by the poor stability of monomethyl succinate chloride when the starting material is used. Specifically, since the problem of poor stability of monomethyl succinate chloride is overcome, the generation of impurities such as succinic acid, monomethyl succinate, and dimethyl succinate caused by the degradation of monomethyl succinate chloride is effectively avoided, thereby effectively avoiding the generation of by-products in the subsequent reaction process.

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

[0045] (3) The preparation method of 5-aminolevulinic acid hydrochloride provided in the present application involves classic and traditional reactions, and the raw materials are easily available and low in cost, and it is easy to realize industrial production. DETAILED DESCRIPTION

[0046] In order to further explain the technical means and results taken by the present application to achieve the predetermined invention purpose, the specific implementation methods, technical solutions and features of the present application are described in detail below with preferred embodiments. The specific features, structures, or characteristics of the multiple embodiments in the following description can be combined in any suitable form.

[0047] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0048] The synthetic route of 5-aminolevulinic acid hydrochloride provided in the embodiment of the present invention is as follows:

[0049]

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

[0051] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0052] Example 1

[0053] Prepare 5-aminolevulinic acid hydrochloride as follows:

[0054] (1) Preparation of intermediate 01:

[0055] Add 600mL of 10% sodium hydroxide solution to the reactor, control the temperature to 20°C, add about 60g of glycine, stir evenly, add about 72g of benzoyl chloride, and stir at 20°C until the reaction is completed. Take about 86.0g of hydrochloric acid, add dropwise to the reactor to adjust the pH value to 2.5, control the temperature to 5°C, keep warm and stir, precipitate solid, centrifuge, and take solid. Add about 930.0g of deionized water and centrifuged solid to the reactor, control the temperature to 70°C, keep warm and stir until the reaction is completed, cool to 20°C, centrifuge, wash the filter cake with deionized water and ethyl acetate respectively, and obtain intermediate 01 (hippuric acid). The content of intermediate 01 is 99.0%, and the yield is 90.5%.

[0056] (2) Preparation of intermediate 02:

[0057] Take about 200.0g of monomethyl succinate, about 0.20g of N,N-dimethylformamide and about 400.0g of toluene and add them into a reaction kettle, and heat it to 55°C; add about 278.0g of thionyl chloride, heat it to 75°C, keep stirring until the reaction is completed, desolventize under reduced pressure, add toluene and continue to desolventize under reduced pressure until there is no fraction, and the obtained intermediate 02 (monomethyl succinate chloride) is set aside.

[0058] (3) Preparation of intermediate 03:

[0059] Within 10 hours after the completion of step (2), add the intermediate 01 (about 120 g) obtained in step (1) and about 415.0 g of 4-methylpyridine to a reaction kettle, cool to 10° C., dropwise add the intermediate 02 (about 260 g) obtained in step (2), and stir until the reaction is completed to obtain a reaction mother liquor. Add deionized water to another reaction kettle, dropwise add the reaction mother liquor at 10° C., continue to slowly dropwise add hydrochloric acid until the pH value is 1.5, centrifuge, and wash the filter cake with deionized water to obtain a crude product;

[0060] The crude product and about 500.0 g of ethyl acetate were added to a reaction kettle, the temperature was controlled at 10°C, stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain a dry product;

[0061] Add about 750.0g of N,N-dimethylacetamide and the above-mentioned dried product into a reaction kettle, control the temperature to 10°C, keep warm and stir, add about 10g of activated carbon, continue to keep warm and stir, filter press, wash the filter cake with deionized water, centrifuge, and wash the filter cake with deionized water; the solid after washing and ethyl acetate are added into a reaction kettle, control the temperature to 10°C, stir, centrifuge, and wash the filter cake with ethyl acetate to obtain intermediate 03(C 14 H 13 NO5).

[0062] (4) Preparation of intermediate 04:

[0063] Take about 267.0g of hydrochloric acid and about 55.0g of deionized water and add them to the reaction kettle, stir evenly, add the hydrochloric acid solution of intermediate 03 prepared in step (3) dropwise, control the temperature to 70°C, keep warm and stir until the reaction is completed, cool to room temperature, filter press, and wash with deionized water; take the filtrate, continue to extract with dichloromethane twice (about 250g each time), and concentrate the aqueous phase obtained by extraction under reduced pressure at 75°C several times until there is no fraction;

[0064] After the reduced pressure concentration is completed, deionized water is added to dissolve and clarify, and activated carbon is continued to be added. The mixture is stirred at room temperature, filtered, washed with acetone, the solution is combined, and the solid is collected and dried in vacuo at 25°C to obtain intermediate 04 (crude 5-aminolevulinic acid hydrochloride).

[0065] (5) Product refining:

[0066] Take about 10.0g of hydrochloric acid and about 24.5g of deionized water and add them to a reaction kettle. After stirring evenly, add the intermediate 04 prepared in step (4), keep warm at 20°C for reaction, add about 1.0g of activated carbon, stir at 20°C, filter press, wash with deionized water and acetone; control the temperature to 20°C, keep warm and stir, centrifuge, wash the filter cake with acetone, collect the solid and dry it in vacuo at 20°C to obtain 5-aminolevulinic acid hydrochloride.

[0067] Example 2

[0068] 5-aminolevulinic acid hydrochloride was prepared according to the method of Example 1, except that when preparing intermediate 03 in step (3) of this example, the temperature of each operation was controlled to be 0° C. Specifically, step (3) of this example is as follows:

[0069] Within 10 hours after the completion of step (2), add the intermediate 01 (about 120 g) obtained in step (1) and about 415.0 g of 4-methylpyridine to a reaction kettle, cool to 0°C, dropwise add the intermediate 02 (about 260 g) obtained in step (2), and stir until the reaction is completed to obtain a reaction mother liquor. Add deionized water to another reaction kettle, dropwise add the reaction mother liquor at 0°C, continue to slowly dropwise add hydrochloric acid until the pH value is 1.5, centrifuge, and wash the filter cake with deionized water to obtain a crude product;

[0070] The crude product and about 500.0 g of ethyl acetate were added to a reaction kettle, the temperature was controlled to 0°C, stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain a dry product;

[0071] Add about 750.0g of N,N-dimethylacetamide and the above-mentioned dried product into a reaction kettle, control the temperature to 0°C, keep warm and stir, add about 10g of activated carbon, continue to keep warm and stir, filter press, wash the filter cake with deionized water, centrifuge, and wash the filter cake with deionized water; the solid after washing and ethyl acetate are added into a reaction kettle, control the temperature to 0°C, stir, centrifuge, and wash the filter cake with ethyl acetate to obtain intermediate 03(C 14 H 13 NO5).

[0072] Example 3

[0073] 5-aminolevulinic acid hydrochloride was prepared according to the method of Example 1, except that when preparing intermediate 03 in step (3) of this example, the temperature of each operation was controlled to be 20° C. Specifically, step (3) of this example is as follows:

[0074] Within 10 hours after the completion of step (2), add the intermediate 01 (about 120 g) obtained in step (1) and about 415.0 g of 4-methylpyridine to a reaction kettle, cool to 20° C., dropwise add the intermediate 02 (about 260 g) obtained in step (2), and stir until the reaction is completed to obtain a reaction mother liquor. Add deionized water to another reaction kettle, dropwise add the reaction mother liquor at 20° C., continue to slowly dropwise add hydrochloric acid until the pH value is 1.5, centrifuge, and wash the filter cake with deionized water to obtain a crude product;

[0075] The crude product and about 500.0 g of ethyl acetate were added to a reaction kettle, the temperature was controlled at 20°C, stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain a dry product;

[0076] About 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product were added to a reaction kettle, the temperature was controlled at 20°C, the mixture was stirred at this temperature, about 10 g of activated carbon was added, the mixture was stirred at this temperature, the filter cake was washed with deionized water, centrifuged, and the filter cake was washed with deionized water; the solid after washing was added to a reaction kettle together with ethyl acetate, the temperature was controlled at 20°C, the mixture was stirred, centrifuged, and the filter cake was washed with ethyl acetate to obtain intermediate 03(C 14 H 13 NO5).

[0077] Example 4

[0078] 5-aminolevulinic acid hydrochloride was prepared according to the method of Example 1, except that, when preparing intermediate 03 in step (3) of this example, the temperature of each operation was controlled to be room temperature (25° C.). Specifically, step (3) of this example is as follows:

[0079] Within 10 hours after the completion of step (2), the intermediate 01 (about 120 g) obtained in step (1) and about 415.0 g of 4-methylpyridine were added to a reaction kettle, and the intermediate 02 (about 260 g) obtained in step (2) was added dropwise at room temperature (25° C.), and stirred until the reaction was completed to obtain a reaction mother liquor. Deionized water was added to another reaction kettle, and the reaction mother liquor was added dropwise at room temperature (25° C.), and hydrochloric acid was slowly added dropwise until the pH value was 1.5, centrifuged, and the filter cake was washed with deionized water to obtain a crude product;

[0080] The crude product and about 500.0 g of ethyl acetate were added to a reaction kettle, stirred at room temperature (25°C), centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain a dry product;

[0081] Add about 750.0 g of N,N-dimethylacetamide and the above-mentioned dried product into a reaction kettle, keep warm and stir at room temperature (25°C), add about 10 g of activated carbon, continue to keep warm and stir, filter press, wash the filter cake with deionized water, centrifuge, and wash the filter cake with deionized water; the solid after washing and ethyl acetate are added into a reaction kettle together, stirred at room temperature (25°C), centrifuged, and the filter cake is washed with ethyl acetate to obtain intermediate 03 (C 14 H 13 NO5).

[0082] Comparative Example 1

[0083] Prepare 5-aminolevulinic acid hydrochloride as follows:

[0084] (1) 120.0 g of hippuric acid and about 415.0 g of 4-methylpyridine were added to a reaction kettle, cooled to 10° C., 260 g of succinic acid monomethyl chloride was added dropwise, and stirred until the reaction was completed to obtain a reaction mother liquor. Deionized water was added to another reaction kettle, and the reaction mother liquor was added dropwise at 10° C., and hydrochloric acid was slowly added dropwise until the pH value was 1.5, centrifuged, and the filter cake was washed with deionized water to obtain a crude product;

[0085] The crude product and about 500.0 g of ethyl acetate were added to a reaction kettle, the temperature was controlled at 10°C, stirred, centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain a dry product;

[0086] Add about 750.0g of N,N-dimethylacetamide and the above-mentioned dried product into a reaction kettle, control the temperature to 10°C, keep warm and stir, add about 10g of activated carbon, continue to keep warm and stir, filter press, wash the filter cake with deionized water, centrifuge, and wash the filter cake with deionized water; the solid after washing and ethyl acetate are added into a reaction kettle, control the temperature to 10°C, stir, centrifuge, and wash the filter cake with ethyl acetate to obtain intermediate C 14 H 13 NO5.

[0087] (2) Add about 267.0 g of hydrochloric acid and about 55.0 g of deionized water into a reaction kettle, stir evenly, and dropwise add the intermediate C prepared in step (2) 14 H 13 NO5 hydrochloric acid solution, control the temperature to 70℃, keep warm and stir until the reaction is completed, cool to room temperature, filter press, and wash with deionized water; take the filtrate, continue to extract with dichloromethane twice (about 250g each time), and the aqueous phase obtained by extraction is concentrated under reduced pressure at 75℃ several times until there is no fraction;

[0088] After the reduced pressure concentration is completed, deionized water is added to dissolve and clarify, and activated carbon is continued to be added. The mixture is stirred at room temperature, filtered, washed with acetone, the solution is combined, and the solid is collected and dried in vacuo at 25°C to obtain a crude 5-aminolevulinic acid hydrochloride.

[0089] (3) Add about 10.0 g of hydrochloric acid and about 24.5 g of deionized water into a reaction kettle, stir evenly, add the crude 5-aminolevulinic acid hydrochloride prepared in step (4), keep warm at 20° C. for reaction, add about 1.0 g of activated carbon, stir at 20° C., filter press, and wash with deionized water and acetone; control the temperature to 20° C., keep warm and stir, centrifuge, wash the filter cake with acetone, collect the solid and dry it in vacuo at 20° C. to obtain 5-aminolevulinic acid hydrochloride.

[0090] Comparative Example 2

[0091] Prepare 5-aminolevulinic acid hydrochloride as follows:

[0092] (1) 120 g of hippuric acid and about 415.0 g of 4-methylpyridine were added to a reaction kettle, 260 g of succinic acid monomethyl chloride was added dropwise at room temperature (25°C), and the reaction was stirred until the reaction was completed to obtain a reaction mother liquor. Deionized water was added to another reaction kettle, the reaction mother liquor was added dropwise at room temperature (25°C), and hydrochloric acid was slowly added dropwise until the pH value was 1.5, centrifuged, and the filter cake was washed with deionized water to obtain a crude product;

[0093] The crude product and about 500.0 g of ethyl acetate were added to a reaction kettle, stirred at room temperature (25°C), centrifuged, the filter cake was washed with about 240.0 g of ethyl acetate, and dried under reduced pressure to obtain a dry product;

[0094] Add about 750.0g of N,N-dimethylacetamide and the above-mentioned dried product into a reaction kettle, keep it warm and stir at room temperature (25°C), add about 10g of activated carbon, continue to keep it warm and stir, filter press, wash the filter cake with deionized water, centrifuge, and wash the filter cake with deionized water; the solid after washing and ethyl acetate are added into a reaction kettle together, stirred at room temperature (25°C), centrifuged, and the filter cake is washed with ethyl acetate to obtain intermediate C 14 H 13 NO5.

[0095] (2) Add about 267.0 g of hydrochloric acid and about 55.0 g of deionized water into a reaction kettle, stir evenly, and dropwise add the intermediate C prepared in step (2) 14 H 13 NO5 hydrochloric acid solution, control the temperature to 70℃, keep warm and stir until the reaction is completed, cool to room temperature, filter press, and wash with deionized water; take the filtrate, continue to extract with dichloromethane twice (about 250g each time), and the aqueous phase obtained by extraction is concentrated under reduced pressure at 75℃ several times until there is no fraction;

[0096] After the reduced pressure concentration is completed, deionized water is added to dissolve and clarify, and activated carbon is continued to be added. The mixture is stirred at room temperature, filtered, washed with acetone, the solution is combined, and the solid is collected and dried in vacuo at 25°C to obtain a crude 5-aminolevulinic acid hydrochloride.

[0097] (3) Add about 10.0 g of hydrochloric acid and about 24.5 g of deionized water into a reaction kettle, stir evenly, add the crude 5-aminolevulinic acid hydrochloride prepared in step (4), keep warm at 20° C. for reaction, add about 1.0 g of activated carbon, stir at 20° C., filter press, and wash with deionized water and acetone; control the temperature to 20° C., keep warm and stir, centrifuge, wash the filter cake with acetone, collect the solid and dry it in vacuo at 20° C. to obtain 5-aminolevulinic acid hydrochloride.

[0098] Experimental Example 1

[0099] Detect the intermediate C in Examples 1-4 and Comparative Examples 1-2 respectively14 H 13 The purity and yield of NO5 and the test results are shown in Table 1.

[0100] Table 1 Intermediate C in Examples 1-4 and Comparative Examples 1-2 14 H 13 Purity and yield of NO5

[0101] <![CDATA[C 14 H 13 NO5 sample]]> purity,% RRT0.74 impurities, % Other impurities, % Yield, % Example 1 98.7％ 0.5％ 0.1％ 45.0％ Example 2 99.5％ 0.2％ 0.1％ 48.1％ Example 3 98.2％ 1.0％ 0.3％ 42.8％ Example 4 95.5％ 2.0％ 1.0％ 17.1％ Comparative Example 1 95.0％ 2.5％ 2.5％ 22.0％ Comparative Example 2 94.4％ 3.5％ 2.8％ 15.3％

[0102] Note: Purity limit: ≥97.0%;

[0103] RRT0.74 (relative retention time 0.74) impurity limit: ≤2.0%;

[0104] Other impurity limits: ≤1.0%;

[0105] Yield calculation:

[0106]

[0107] Experimental Example 2

[0108] The purity and yield of the 5-aminolevulinic acid hydrochloride finally prepared in Examples 1-4 and Comparative Examples 1-2 were tested respectively, and the test results are shown in Table 2.

[0109] Table 2 Purity and yield of 5-aminolevulinic acid hydrochloride in Examples 1-4 and Comparative Examples 1-2

[0110]

[0111]

[0112] Yield calculation:

[0113]

[0114] The above is only a preferred specific implementation of the present application; however, the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solution and its improved ideas of the present application within the technical scope disclosed in the present application, which should be included in the protection scope of the present application.

Claims

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

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

3. The preparation method according to claim 1, characterized in that: In step S2, the succinic acid monomethyl 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 at 0-20°C.

4. The preparation method according to claim 3, characterized in that: In step S2, the succinic acid monomethyl 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 chloride obtained in step S1 are added to a reaction kettle, stirred at 0-20°C until the reaction is completed, cooled and hydrochloric acid is added dropwise to adjust the pH to 1-2, the precipitated solid is separated, dried, pulped with ethyl acetate, and then crystallized and decolorized to obtain C 14 H 13 NO5.

5. The preparation method according to claim 4, characterized in that: In parts by weight, the ratio of hippuric acid, 4-methylpyridine and succinic acid monomethyl chloride 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 chloride obtained in step S1 is coupled with hippuric acid to obtain C 14 H 13 NO5, including: S201, adding the hippuric acid and 4-methylpyridine into a reaction kettle, controlling the temperature to 0-20° C., dropwise adding the succinic acid monomethyl chloride obtained in step S1, and stirring until the reaction is completed to obtain a reaction mother liquor; S202, dropping the reaction mother liquid into water at 0-20° C., adding hydrochloric acid to adjust the pH to 1-2, separating and washing the precipitated solid to obtain a first intermediate crude product; S203, adding the first intermediate crude product and ethyl acetate into a reaction kettle, controlling the temperature to 0-20° C., stirring, solid-liquid separation, washing, and drying to obtain a second intermediate crude product; S204, crystallizing and decolorizing the second intermediate crude product 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, succinic acid monomethyl ester and thionyl chloride are subjected to a chlorination reaction to obtain succinic acid monomethyl ester chloride, comprising: Monomethyl succinate, thionyl chloride, toluene and a catalyst are added into a reaction kettle, reacted completely at 65-85° C., and concentrated to remove toluene and excess thionyl chloride to obtain monomethyl succinate chloride.

8. The preparation method according to claim 7, characterized in that: The catalyst includes at least one of N,N-dimethylformamide, N-methylpyrrolidone, 2,6-diisopropylaniline and N,N-diisopropylethylamine; And / or, in parts 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 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 obtained solid product is re-dissolved in water and acetone is added dropwise, the precipitated solid is separated, washed and dried; The dried product was crystallized in dilute hydrochloric acid to give 5-aminolevulinic acid hydrochloride.

10. The preparation method according to claim 1, characterized in that: The preparation method further comprises the step of preparing the hippuric acid: glycine and benzoyl chloride are reacted in a sodium hydroxide solution, after the reaction is completed, the temperature is lowered and hydrochloric acid is added dropwise to adjust the pH value to 2-3, the precipitated solid is separated, and the wet filter cake is pulped with hot water to remove the impurity benzoic acid to obtain the hippuric acid; Optionally, in parts by weight, the ratio of glycine to benzoyl chloride is (0.8-1.2):(0.96-1.44).

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