Synthesis method of 5-aminolevulinic acid hydrochloride

Abstract

The invention discloses a synthesis method of 5-aminolevulinic acid hydrochloride, which comprises the following steps: S1, in the presence of a perfluoromethanesulfonic acid metal complex catalyst, carrying out esterification reaction on levulinic acid in ethanol, then adding organic amine, inorganic bromide and 3-PyHBr3 into the reaction liquid, and carrying out bromination reaction to obtain 5-aminolevulinic acid hydrochloride; separating to obtain a 5-bromolevulinic acid ethyl ester crude product; s2, carrying out reaction on the 5-bromoethyl levulinate crude product and succinimide potassium salt, and separating to obtain a 5-succinimide substituted ethyl levulinate crude product; s3, the 5-succinimide substituted ethyl levulinate crude product is subjected to a hydrolysis reaction in the presence of hydrochloric acid, and 5-aminolevulinic acid hydrochloride is obtained. The method has the beneficial effects of low raw material cost, simple process, simple post-treatment, high total yield, mild reaction conditions and environmental protection.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing 5-aminolevulinic acid hydrochloride. Background Art

[0002] 5-Aminolevulinic acid (5-ALA) is an amino acid widely present in the cells of animals, plants and microorganisms. It is a precursor compound for the synthesis of tetrapyrrole compounds in organisms, such as heme, chlorophyll, vitamin B12 and porphyrin. 5-ALA has a variety of physiological effects in plants, such as promoting photosynthesis and tissue differentiation, regulating respiration, stimulating cell peroxidation, etc. It can be used as a green and environmentally friendly pesticide insecticide, photoactivated herbicide and plant growth regulator. In the medical field, 5-ALA has the pharmacological effect of selectively killing cancer cells. It is a second-generation photodynamic therapy drug with significant therapeutic effects in the treatment of skin cancer, pharyngeal cancer, oral cancer, bladder cancer, duodenal cancer, glioma, pancreatic cancer, breast cancer, etc. It can also be used for the diagnosis of heavy metal poisoning, porphyria and the treatment of fungal diseases and rheumatoid arthritis. However, 5-ALA has unstable chemical properties and needs to be stored at low temperature, dark and oxygen-free conditions. Protonating the amino group in the 5-ALA structure to form its hydrochloride can greatly improve its stability. Currently, the products available on the market are mainly in the form of its hydrochloride.

[0003] 5-ALA can be synthesized by biosynthesis and chemical synthesis. Biosynthesis has the advantages of good environmental compatibility and cheap and readily available raw materials, but it still has the disadvantages of low yield, difficult to control biochemical reaction conditions and difficulty in large-scale industrial production. Chemical synthesis mainly uses succinic anhydride derivatives, furfural, tetrahydrofurfurylamine, furfural, glycine, polypeptides, succinic acid and hippuric acid as raw materials, but it also has the disadvantages of long synthesis route, high cost, difficult separation and purification and low total yield.

[0004] Levulinic acid is a green platform molecule obtained from biomass resources. It is cheap, easy to obtain, and has good reaction performance. It can synthesize a variety of functional downstream products. The preparation of 5-ALA using levulinic acid as raw material has the advantages of wide raw material sources and low cost. It is one of the most promising methods for the preparation of 5-ALA in industrial application. However, it also has shortcomings such as low total yield, by-product generation and difficulty in separation and purification. Therefore, the development of a green, economical and efficient method for the preparation of 5-ALA using levulinic acid as raw material has important theoretical research significance and practical application value. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the above background technology and provide a method for synthesizing 5-aminolevulinic acid hydrochloride with high yield and low cost.

[0006] In order to solve the above technical problems, the technical solution proposed by the present invention is: A method for synthesizing 5-aminolevulinic acid hydrochloride comprises the following steps: S1. Under an inert protective atmosphere, in the presence of a perfluoromethanesulfonic acid metal complex catalyst, esterify levulinic acid in ethanol, and then add an organic amine, an inorganic bromide and 3-PyHBr to the reaction solution. 3 , carry out bromination reaction, and separate and obtain crude ethyl 5-bromolevulinate; S2. Under an inert protective atmosphere, reacting the crude product of ethyl 5-bromolevulinate with potassium succinimide to separate and obtain a crude product of ethyl 5-succinimide-substituted levulinate; S3. Under an inert protective atmosphere, the crude product of 5-succinimide-substituted ethyl levulinate is hydrolyzed in the presence of hydrochloric acid to obtain 5-aminolevulinic acid hydrochloride.

[0007] As a further improvement, the perfluoromethanesulfonic acid metal complex catalyst is selected from one or more of the following compounds: (CF 3 SO 3 ) 2 Fe, (CF 3 SO 3 ) 2 Co、(CF 3 SO 3 ) 2 Zn, (CF 3 SO 3 ) 2 Cu, (CF 3 SO 3 ) 2 Ni、CF 3 SO 3 Ag, (CF 3 SO 3 ) 2 Sn、(CF 3 SO 3 ) 2 Hf、Cp 2 (CF 3 SO 3 ) 2 Ti、Cp 2 (CF 3 SO 3 ) 2 Ti-THF.

[0008] As a further improvement, the organic amine is selected from one or more of the following compounds: triethylamine, diisopropylamine, urea, formamide, acetamide, dimethylformamide, acetanilide, and caprolactam.

[0009] As a further improvement, the inorganic bromide is selected from one or more of the following compounds: CuBr 2 、NaBr、KBr、FeBr 3 MgBr 2 、NiBr 2 , CaBr 2 ,CoBr 2 .

[0010] As a further improvement, the temperature of the esterification reaction is 25-75°C, and the temperature of the bromination reaction is 0-60°C.

[0011] As a further improvement, the temperature for the reaction of ethyl 5-bromolevulinate and potassium succinimide is 25-100°C.

[0012] As a further improvement, the reaction solvent of the hydrolysis reaction is water; the volume ratio of the solvent water and hydrochloric acid added is (4-6):1, and the concentration of the hydrochloric acid is 5-8 N.

[0013] As a further improvement, the hydrolysis reaction temperature is 50-110°C.

[0014] As a further improvement, after the hydrolysis reaction is completed, the product is filtered, ethyl acetate is added for separation and extraction, and the solvent is dried to obtain a crude product.

[0015] As a further improvement, methanol is added to the crude product, the temperature is raised to above 40° C. and stirred, then acetone is added, the product is cooled and stirred, filtered, and dried to obtain 5-aminolevulinic acid hydrochloride.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The invention uses levulinic acid as a starting material, performs an esterification reaction catalyzed by a perfluoromethanesulfonic acid metal complex in an ethanol solvent to generate ethyl levulinate, and then reacts with an inorganic bromide / 3-PyHBr in the presence of an organic amine to produce ethyl levulinate. 3 The product is subjected to bromination reaction to generate ethyl 5-bromolevulinate, and finally reacted with potassium succinimide to obtain the target product 5-ALA hydrochloride.

[0017] The present invention develops a new synthesis route of 5-aminolevulinic acid (5-ALA) hydrochloride, uses cheap reagents as raw materials, and through simple and efficient conversion, 5-ALA hydrochloride is prepared at low cost, green and efficient. The advantages are: (1) low raw material cost, simple process and simple post-treatment; (2) the catalyst has good catalytic performance in the esterification reaction, high chemical selectivity in the bromination reaction and high total yield; (3) mild reaction conditions and green and environmentally friendly. DETAILED DESCRIPTION

[0018] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively and carefully in combination with preferred embodiments below, but the protection scope of the present invention is not limited to the following specific embodiments.

[0019] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0020] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0021] The synthesis method of 5-aminolevulinic acid hydrochloride of the present invention has the following synthesis route:

[0022] In some embodiments, the synthesis method of the present invention comprises the following steps: S1. Under an inert protective atmosphere, in the presence of a perfluoromethanesulfonic acid metal complex catalyst, esterification reaction is carried out on levulinic acid (1) in ethanol, and then an organic amine, an inorganic bromide and pyridinium tribromide (3-PyHBr) are added to the reaction solution. 3 ), and bromination reaction was carried out to separate and obtain the crude product of ethyl 5-bromolevulinate (2).

[0023] In some embodiments, the perfluoromethanesulfonic acid metal complex catalyst is one or more of the following compounds: iron trifluoromethanesulfonate ((CF 3 SO 3 ) 2 Fe), cobalt trifluoromethanesulfonate (CF 3 SO 3 ) 2 Co), zinc trifluoromethanesulfonate ((CF 3 SO 3 ) 2 Zn), copper trifluoromethanesulfonate (CF 3 SO 3 ) 2 Cu), nickel trifluoromethanesulfonate ((CF 3 SO 3 ) 2 Ni), silver trifluoromethanesulfonate (CF 3 SO 3 Ag), tin trifluoromethanesulfonate ((CF 3 SO 3 ) 2 Sn), hafnium trifluoromethanesulfonate ((CF 3 SO 3 )2 Hf), bis(trifluoromethanesulfonate) titanocene (Cp 2 (CF 3 SO 3 ) 2 Ti), bis(trifluoromethanesulfonic acid) zirconocene tetrahydrofuran complex (Cp 2 (CF 3 SO 3 ) 2 Ti-THF). Preferably Cp 2 (CF 3 SO 3 ) 2 Ti or (CF 3 SO 3 ) 2 Sn, the yield is higher. The molar amount of the perfluoromethanesulfonic acid metal complex catalyst added is 1-20% of the molar amount of levulinic acid (1), preferably 3-8%.

[0024] In some embodiments, the organic amine is one or more of the following compounds: triethylamine, diisopropylamine, urea, formamide, acetamide, dimethylformamide, acetanilide, caprolactam. Caprolactam is preferred, and the yield is higher. The molar amount of the organic amine added is 15-25% of the molar amount of levulinic acid (1). The role of the organic amine is: the organic amine has a certain alkalinity, which is conducive to the departure of the α hydrogen atom on the carbonyl α carbon atom, thereby promoting the reaction. In addition, the organic amine can react with the by-product hydrogen bromide to react with an acid-base neutralization reaction, which is conducive to the reaction moving in the positive direction.

[0025] In some embodiments, the inorganic bromide is one or more of the following compounds: CuBr 2 、NaBr、KBr、FeBr 3 MgBr 2 、NiBr 2 , CaBr 2 ,CoBr 2 CuBr is preferred 2 , with a higher yield. Inorganic bromide and 3-PyHBr 3 As a brominating agent, it synergistically improves the yield. The molar amount of inorganic bromide added is 15-25% of the molar amount of levulinic acid (1).

[0026] In some embodiments, levulinic acid (1) is reacted with a bromination reagent 3-PyHBr 3 The molar ratio is 1:(0.9-1.2).

[0027] In some embodiments, the temperature for the esterification reaction of levulinic acid (1) and ethanol catalyzed by the perfluoromethanesulfonic acid metal complex is 25-75°C, and the reaction time is 0.5-5 h. The temperature for the bromination reaction is 0-60°C, and the reaction time is 3-10 h.

[0028] In some embodiments, after the bromination reaction is completed, separation extraction is performed, and the solvent is dried and spin-dried to obtain a crude product of 5-bromolevulinic acid ethyl ester (2). The solvent system used for separation extraction is one of water / dichloromethane, water / ethyl acetate, water / ether, water / toluene, saline / dichloromethane, saline / ethyl acetate, saline / ether, and saline / toluene.

[0029] S2. Under an inert protective atmosphere, the crude product of ethyl 5-bromolevulinate (2) is reacted with potassium succinimide to separate and obtain the crude product of ethyl 5-succinimide-substituted levulinate (3).

[0030] In some embodiments, the solvent for the reaction of ethyl 5-bromolevulinate (2) with potassium succinimide is one or more of acetone, acetonitrile, DMF, DMSO, THF, 1,4-dioxane, dichloromethane, methanol, ethanol, isopropanol, n-butanol, and diethyl ether.

[0031] In some embodiments, the temperature for the reaction of ethyl 5-bromolevulinate (2) with potassium succinimide is 25-100° C., and the reaction time is 2-12 h.

[0032] In some embodiments, 5-bromolevulinic acid ethyl ester (2) is reacted with succinimide potassium salt, filtered, extracted by separation, dried, and the solvent is spin-dried to obtain a crude product of 5-succinimide-substituted levulinic acid ethyl ester (3). The solvent system used for separation extraction is one of water / dichloromethane, water / ethyl acetate, water / ether, water / toluene, saline / dichloromethane, saline / ethyl acetate, saline / ether, and saline / toluene.

[0033] S3. Under an inert protective atmosphere, the crude product of 5-succinimide-substituted ethyl levulinate (3) is hydrolyzed in the presence of hydrochloric acid to obtain 5-ALA hydrochloride (4).

[0034] In some embodiments, the hydrolysis of 5-succinimide-substituted ethyl levulinate (3) is performed using dilute hydrochloric acid, the concentration of which is 5-8 N (5-8 M), preferably 7-8 N, with a higher yield. The solvent used for the hydrolysis is one of water, methanol, ethanol, and n-butanol, preferably water, and the volume ratio of water to dilute hydrochloric acid is (4-6):1, preferably 5:1.

[0035] In some embodiments, the hydrolysis temperature is 50-110° C. and the time is 10-24 h.

[0036] In some embodiments, after the hydrolysis reaction is completed, the product is filtered, ethyl acetate is added for separation and extraction, and the solvent is dried to obtain a crude product, which is then heated and pulped for purification, and the solvent used for pulping and purification is one or more of methanol, ethyl acetate, 1,4-dioxane, dichloromethane, ethanol, isopropanol, ether, THF, acetonitrile, acetone, and toluene. Preferably, methanol is added to the crude product, the temperature is raised to above 40° C. and stirred, and then acetone is added, cooled and stirred, filtered, and dried to obtain 5-ALA hydrochloride (4).

[0037] Embodiment 1: Add succinimide (19.8180 g, 200.0 mmol), KOH (12.3432 g, 220 mmol) and 300 mL of ethanol into a 500 mL three-necked flask. React for 5 h at 60 °C under nitrogen protection. After the reaction is completed, cool to room temperature, filter, wash the filter cake with a small amount of ethanol, and dry the filter cake to obtain the product succinimide potassium salt, with a mass of 25.2411 g.

[0038] In a 250 mL three-necked flask, add levulinic acid (1) (0.5806 g, 5.0 mmol), Cp 2 (CF 3 SO 3 ) 2 Ti (0.1190 g, 0.25 mmol) and 50 mL of ethanol were added. The reaction was carried out at 60 °C for 4 h under nitrogen protection. CuBr 2 (0.2234 g, 1.0 mmol), caprolactam (0.1132 g, 1.0 mmol) and 3-PyHBr were added in three portions 3 (1.6631 g, 5.2 mmol). The reaction was continued at 60°C for 6 h under nitrogen protection. After the reaction was completed, the solvent was dried by spin drying, and the reaction mixture was transferred to a separatory funnel. Water (40 mL) and dichloromethane (20 mL) were added for separation and extraction. The aqueous phase was extracted twice with dichloromethane (10 mL). The organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was spin dried to obtain the crude product of ethyl 5-bromolevulinate (2), which was directly used in the next step.

[0039] To the crude product of 5-bromolevulinic acid ethyl ester (2), potassium succinimide (0.8231 g, 6.0 mmol) and acetone (50 mL) were added. Under nitrogen protection, the reaction was refluxed for 8 h. After the reaction was completed, the filtrate was filtered and the solvent was dried and transferred to a separatory funnel. Water (50 mL) and dichloromethane (20 mL) were added for separation and extraction. The aqueous phase was extracted twice with dichloromethane (10 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product of 5-succinimide-substituted levulinic acid ethyl ester (3), which was directly used in the next step.

[0040] Dilute hydrochloric acid (4 mL, 7 N) and water (20 mL) were added to the crude product of 5-succinimide-substituted ethyl levulinate (3). Under nitrogen protection, the reaction was refluxed for 12 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with a small amount of water, the filtrate was transferred to a separatory funnel, 100 mL of ethyl acetate was added, and the filtrate was separated and extracted. The aqueous phase was washed twice with 50 mL of ethyl acetate, and the ethyl acetate solvent was dried to obtain a solid crude product of 5-aminolevulinic acid (5-ALA) hydrochloride. 8 mL of anhydrous methanol was added to the crude product, the temperature was raised to 40°C and stirred for 3 h, 10 mL of acetone was added, the heating was turned off, the mixture was cooled to room temperature, stirring was continued for 6 h, suction filtered, the filter cake was washed with acetone, and the filter cake was dried to obtain a white solid, which was the product 5-aminolevulinic acid (5-ALA) hydrochloride (4), with a mass of 0.3042 g and a total molar yield of 36.3%.

[0041] The target product 4 has the following structural formula:

[0042] 1 H NMR (400 MHz, D 2 O): δ 4.13‒4.08 (m, 4H), 2.87 (t, J = 6.3 Hz, 2H),2.65 (t, J = 6.2 Hz, 2H), 1.19 (t, J = 8.0 Hz, 2H). Embodiment 2: This embodiment is basically the same as embodiment 1, except that: (CF 3 SO 3 ) 2 Fe replaces Cp 2 (CF 3 SO 3 ) 2 Ti as a catalyst.

[0043] Embodiment 3: This embodiment is basically the same as embodiment 1, except that: (CF 3 SO 3 ) 2 Ni replaces Cp 2 (CF 3 SO 3 ) 2 Ti as a catalyst.

[0044] Embodiment 4: This embodiment is basically the same as embodiment 1, except that: (CF 3 SO 3 ) 2 Cu replaces Cp 2 (CF 3 SO 3 ) 2 Ti as a catalyst.

[0045] Embodiment 5: This embodiment is basically the same as embodiment 1, except that: (CF 3 SO 3 ) 2 Sn instead of Cp 2 (CF 3 SO 3 ) 2 Ti as a catalyst.

[0046] Embodiment 6: This embodiment is substantially the same as embodiment 1, except that no inorganic bromide is added in the bromination reaction.

[0047] Embodiment 7: This embodiment is substantially the same as embodiment 1, except that no organic amine compound is added in the bromination reaction.

[0048] Embodiment 8: This embodiment is substantially the same as embodiment 1, except that no organic bromide and organic amine compound are added in the bromination reaction.

[0049] Embodiment 9: This example is substantially the same as Example 1, except that triethylamine is used instead of caprolactam in the bromination reaction.

[0050] Embodiment 10: This embodiment is substantially the same as embodiment 1, except that urea is used instead of caprolactam in the bromination reaction.

[0051] Embodiment 11: This example is substantially the same as Example 1, except that acetamide is used instead of caprolactam in the bromination reaction.

[0052] Embodiment 12: This example is basically the same as Example 1, except that NaBr is used instead of CuBr in the bromination reaction. 2 .

[0053] Embodiment 13: This embodiment is basically the same as embodiment 1, except that FeBr is used in the bromination reaction. 3 Replace CuBr 2 .

[0054] Embodiment 14: This embodiment is basically the same as embodiment 1, except that MgBr is used in the bromination reaction. 2 Replace CuBr 2 .

[0055] Embodiment 15: This embodiment is basically the same as embodiment 1, except that CoBr is used in the bromination reaction. 2 Replace CuBr 2 .

[0056] Embodiment 16: This example is basically the same as Example 1, except that 5N dilute hydrochloric acid is used instead of 7N dilute hydrochloric acid in the hydrolysis reaction of 5-succinimide-substituted ethyl levulinate (3).

[0057] Embodiment 17: This example is basically the same as Example 1, except that 8N dilute hydrochloric acid is used instead of 7N dilute hydrochloric acid in the hydrolysis reaction of 5-succinimide-substituted ethyl levulinate (3).

[0058] The reaction conditions and yield data of the above examples are shown in Tables 1-3.

[0059] Table 1

[0060] Table 2

[0061] Table 3

[0062] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for synthesizing 5-aminolevulinic acid hydrochloride, characterized in that: The steps include: S1. Under an inert protective atmosphere, in the presence of a perfluoromethanesulfonic acid metal complex catalyst, esterifying levulinic acid in ethanol, then adding an organic amine, an inorganic bromide and 3-PyHBr3 to the reaction solution to carry out a bromination reaction, and separating to obtain a crude product of ethyl 5-bromolevulinate; S2. Under an inert protective atmosphere, reacting the crude product of ethyl 5-bromolevulinate with potassium succinimide to separate and obtain a crude product of ethyl 5-succinimide-substituted levulinate; S3. Under an inert protective atmosphere, the crude product of 5-succinimide-substituted ethyl levulinate is hydrolyzed in the presence of hydrochloric acid to obtain 5-aminolevulinic acid hydrochloride.

2. The method for synthesizing 5-aminolevulinic acid hydrochloride according to claim 1, characterized in that: The perfluoromethanesulfonic acid metal complex catalyst is selected from one or more of the following compounds: (CF3SO3)2Fe, (CF3SO3)2Co, (CF3SO3)2Zn, (CF3SO3)2Cu, (CF3SO3)2Ni, CF3SO3Ag, (CF3SO3)2Sn, (CF3SO3)2Hf, Cp2(CF3SO3)2Ti, Cp2(CF3SO3)2Ti-THF.

3. The method for synthesizing 5-aminolevulinic acid hydrochloride according to claim 1, characterized in that: The organic amine is selected from one or more of the following compounds: triethylamine, diisopropylamine, urea, formamide, acetamide, dimethylformamide, acetanilide, and caprolactam.

4. The method for synthesizing 5-aminolevulinic acid hydrochloride according to claim 1, characterized in that: The inorganic bromide is selected from one or more of the following compounds: CuBr2, NaBr, KBr, FeBr3, MgBr2, NiBr2, CaBr2, CoBr2.

5. The method for synthesizing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 4, characterized in that: The temperature of the esterification reaction is 25-75°C, and the temperature of the bromination reaction is 0-60°C.

6. The method for synthesizing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 4, characterized in that: The temperature for the reaction of ethyl 5-bromolevulinate and potassium succinimide is 25-100°C.

7. The method for synthesizing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 4, characterized in that The reaction solvent of the hydrolysis reaction is water; the volume ratio of the solvent water and hydrochloric acid added is (4-6):1, and the concentration of the hydrochloric acid is 5-8 N.

8. The method for synthesizing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 4, characterized in that: The hydrolysis reaction temperature is 50-110°C.

9. The method for synthesizing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 4, characterized in that: After the hydrolysis reaction is completed, the mixture is filtered, ethyl acetate is added for separation and extraction, and the solvent is dried to obtain a crude product.

10. The method for synthesizing 5-aminolevulinic acid hydrochloride according to claim 9, characterized in that: Methanol is added to the crude product, the temperature is raised to above 40° C. and stirred, then acetone is added, the product is cooled and stirred, filtered, and dried to obtain 5-aminolevulinic acid hydrochloride.

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