Method for preparing 5-aminolevulinic acid step by step through ultrasonic assistance

Abstract

The invention discloses a method for preparing 5-aminolevulinic acid step by step through ultrasonic assistance, which comprises the following steps: firstly, by taking levulinic acid and esterified derivatives thereof as substrates and methanol and acetonitrile as solvents, adding a bromination reagent, and carrying out a 5 # site bromination substitution reaction through ultrasonic assistance dissolution and condensation reflux experiments under the reaction condition of 50 DEG C; the yield of the 5-bromolevulinic acid methyl ester reaction liquid can reach 94% or above; the obtained methyl 5-bromolevulinate reaction solution is purified and then is subjected to a condensation reflux experiment with potassium phthalimide in an ethyl acetate solvent at a certain temperature for a certain period of time to obtain the methyl 5-(phthalimide) levulinate with the yield of 97% or above; 5-(phthalimide) methyl levulinate is purified and then subjected to acidolysis with HCl, and 88% of 5-aminolevulinic acid can be obtained. The method is simple and feasible, a bromination reagent is common and easy to obtain, and reaction conditions are mild; the comprehensive yield of the product is more than 80%, and the method has good industrial potential.

Description

Technical Field

[0001] The invention relates to the technical field of chemical preparation, and in particular to a method for preparing 5-aminolevulinic acid in steps with the assistance of ultrasound. Background Art

[0002] Lignocellulosic biomass is the most abundant biorenewable resource in existence and has great potential for the sustainable production of chemicals and fuels. Therefore, the development of a series of chemical processes based on renewable raw materials, especially the research and development of biomass and biomass-derived chemicals, has attracted people's attention. Among them, 5-aminolevulinic acid is an important precursor molecule for the synthesis of tetrapyridines such as porphyrin, heme, chlorophyll, vitamin B, and plays a wide range of roles in the localization and photodynamic therapy of various cancers. However, at present, 5-aminolevulinic acid is mainly synthesized by microbial production, but the synthesis process is complicated, time-consuming, and costly, making it difficult to achieve large-scale application of 5-aminolevulinic acid. There are also methods for preparing 5-aminolevulinic acid using 2-hydroxypyridine, tetrahydrofuranamine, and furanamine as starting materials, but this route requires strict reaction conditions and it is difficult to avoid the production of toxic intermediates.

[0003] Therefore, in order to solve the above problems, this paper proposes a method for ultrasound-assisted step-by-step preparation of 5-aminolevulinic acid. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, which has a green and sustainable production approach, can make the reaction easy to separate and purify, and has higher industrialization potential.

[0005] In order to achieve the above technical effects, the present invention is implemented by the following technical scheme: a method for preparing 5-aminolevulinic acid by ultrasound-assisted stepwise steps, characterized in that it comprises the following steps:

[0006] S1, taking the reaction raw material and the bromination reagent in a molar ratio of reaction raw material: bromination reagent = 1:3-5, then mixing the reaction raw material and the bromination reagent in a reactor filled with methanol and acetonitrile solvents, heating and condensing reflux reaction at 30-70° C. for 2-4 hours, and then cooling to room temperature to obtain a 5-bromolevulinic acid methyl ester reaction solution with a substrate concentration of 0.001-3 g / mL;

[0007] S2, the molar ratio is 1:1~2.6 = 5-bromolevulinic acid methyl ester reaction solution: potassium phthalimide. Take 5-bromolevulinic acid methyl ester reaction solution and potassium phthalimide, then mix the 5-bromolevulinic acid methyl ester reaction solution and potassium phthalimide in a solvent, react at 30~70°C for 0.5~2.5h, then obtain 5-(phthalimide) levulinic acid methyl ester through a condensation reflux experiment, and then acidolyze it with an acidolysis reagent for 3~7h to generate 5-aminolevulinic acid.

[0008] Furthermore, in S1, the reaction raw materials are levulinic acid and its esterified derivatives with a substrate concentration of 0.001 to 3 g / mL.

[0009] Furthermore, in S1, the bromination reagent is at least one of HBr, CuBr2, FeBr3, NiBr2, and CoBr2.

[0010] Furthermore, in S2, the solvent is at least one of dioxane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.

[0011] Furthermore, in S2, the acidolysis reagent is at least one of hydrochloric acid, acetic acid, hydrofluoric acid, and trifluoromethanesulfonic acid.

[0012] The beneficial effects of the present invention are:

[0013] The invention is simple and feasible, the bromination reagent is common and easy to obtain, the reaction conditions are mild, and 5-aminolevulinic acid with a comprehensive yield of more than 80% is prepared by adopting a step-by-step preparation method; copper bromide with higher selectivity and activity is used to replace traditional liquid bromine as the bromination reagent, and green and pollution-free methanol and acetonitrile are used to replace chloroform as the solvent, so that methyl levulinate is efficiently and selectively catalytically converted into methyl 5-bromolevulinate; methyl 5-bromolevulinate can be converted into methyl 5-(phthalimide)levulinate by the property that methyl 5-bromolevulinate can undergo an amination reaction with potassium phthalimide without a catalyst, and ethyl acetate is used as the reaction solvent, so that the reaction is easy to separate and purify, and the invention has higher industrialization potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0015] Figure 1 is a gas phase diagram of the separated product M5B of Example 3 of the present invention;

[0016] Figure 2 is a gas phase diagram of the separation product M5P of Example 3 of the present invention;

[0017] Figure 3 It is a liquid phase diagram of the separated product 5-ALA in Example 3 of the present invention. DETAILED DESCRIPTION

[0018] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0019] Example 1

[0020] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0021] 0.33 g of levulinic acid and its esterified derivatives (hereinafter referred to as ML) and 2.55 g of copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:3;

[0022] The obtained initial solution was ultrasonically mixed in an ultrasonic cleaner, and the uniformly mixed solvent was heated at 50°C with stirring, condensed and refluxed for reaction for 3 hours, and the yield of 5-bromolevulinic acid methyl ester reaction solution (hereinafter referred to as M5B) was 64%; the purified M5B and potassium phthalimide (hereinafter referred to as KPI) were reacted in ethyl acetate (hereinafter referred to as EA) solvent, n(KPI):n(M5B)=1.8:1, and heated at 110°C with stirring, condensed and refluxed for reaction for 2 hours to obtain 97% of 5-(phthalimide) methyl levulinate (hereinafter referred to as M5P), and the purified M5P was subjected to HCl acid hydrolysis for 5 hours to obtain 88% yield of 5-aminolevulinic acid (hereinafter referred to as 5-ALA).

[0023] Example 2

[0024] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0025] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:2;

[0026] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 78%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and reacted for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0027] Example 3

[0028] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0029] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0030] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C, stirred, condensed and refluxed for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C in EA solvent, n(KPI):n(M5B)=1.8:1, and condensed and refluxed for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0031] Example 4

[0032] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0033] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 2:1;

[0034] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 76%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and reacted for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0035] Example 5

[0036] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0037] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 3:1;

[0038] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 69%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and reacted for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0039] Example 6

[0040] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0041] 0.33 g ML and 1.95 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0042] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 65%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0043] Example 7

[0044] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0045] 0.33 g ML and 2.23 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0046] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C, stirred, condensed and refluxed for 3 hours, and the M5B yield was 85%; the purified M5B and KPI were heated at 110°C in EA solvent, n(KPI):n(M5B)=1.8:1, and condensed and refluxed for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0047] Example 8

[0048] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0049] 0.33 g ML and 2.79 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0050] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 84%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0051] Example 9

[0052] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0053] 0.33 g ML and 3.07 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0054] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 77%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and reacted for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0055] Example 10

[0056] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0057] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0058] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated, stirred, condensed and refluxed at 40°C for 3 hours, and the M5B yield was 60%; the purified M5B and KPI were heated, stirred, condensed and refluxed in EA solvent, n(KPI):n(M5B)=1.8:1, at 110°C for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0059] Embodiment 11

[0060] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0061] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0062] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 45°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 79%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0063] Example 12

[0064] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0065] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0066] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 55°C, stirred, condensed and refluxed for 3 hours, and the M5B yield was 92%; the purified M5B and KPI were heated at 110°C in EA solvent, n(KPI):n(M5B)=1.8:1, and condensed and refluxed for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0067] Embodiment 13

[0068] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0069] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0070] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 60°C, stirred, condensed and refluxed for 3 hours, and the M5B yield was 85%; the purified M5B and KPI were heated at 110°C in EA solvent, n(KPI):n(M5B)=1.8:1, and condensed and refluxed for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0071] Embodiment 14

[0072] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0073] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0074] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C, stirred, condensed and refluxed for 2 hours, and the M5B yield was 78%; the purified M5B and KPI were heated at 110°C in EA solvent, n(KPI):n(M5B)=1.8:1, and condensed and refluxed for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0075] Embodiment 15

[0076] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0077] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0078] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 2.5 hours, and the M5B yield was 87%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and 97% M5P was obtained. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0079] Example 16

[0080] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0081] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0082] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3.5 hours, and the M5B yield was 76%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0083] Embodiment 17

[0084] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0085] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0086] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 4 hours, and the M5B yield was 62%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and reacted for 2 hours to obtain 97% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0087] Embodiment 18

[0088] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0089] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0090] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1:1, and 54% M5P was obtained. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0091] Example 19.

[0092] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0093] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0094] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.4:1, and reacted for 2 hours to obtain 94% M5P. The purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0095] Embodiment 20

[0096] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0097] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0098] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=2.2:1, for 2 hours to obtain 85% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0099] Embodiment 21

[0100] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0101] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0102] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=2.6:1, for 2 hours to obtain 65% M5P, and the purified M5P was acidolyzed with HCl for 5 hours to obtain 5-ALA with a yield of 88%.

[0103] Embodiment 22

[0104] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0105] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0106] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, and 97% M5P was obtained. The purified M5P was acidolyzed with HCl for 3 hours to obtain 5-ALA with a yield of 54%.

[0107] Embodiment 23

[0108] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0109] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0110] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 4 hours to obtain 5-ALA with a yield of 81%.

[0111] Embodiment 24

[0112] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0113] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0114] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 6 hours to obtain 5-ALA with a yield of 78%.

[0115] Embodiment 25

[0116] This embodiment provides a method for preparing 5-aminolevulinic acid in steps assisted by ultrasound, the steps are as follows:

[0117] 0.33 g ML and 2.55 g copper bromide were added to 30 mL of a mixed solvent to obtain an initial solution; the mixed solvent was prepared by mixing methanol and acetonitrile in a molar ratio of methanol:acetonitrile = 1:1;

[0118] The obtained initial liquid was ultrasonically mixed in an ultrasonic cleaner, and the mixed solvent was heated at 50°C with stirring, condensing and refluxing for 3 hours, and the M5B yield was 94%; the purified M5B and KPI were heated at 110°C with stirring, condensing and refluxing in EA solvent, n(KPI):n(M5B)=1.8:1, for 2 hours to obtain 97% M5P, and the purified M5P was acidolyzed with HCl for 7 hours to obtain 5-ALA with a yield of 65%.

[0119] Embodiment 26

[0120] As shown in Table 1, the efficiency of converting ML to M5B in the preparation methods of Examples 1 to 25 is as follows:

[0121]

[0122] Table 1

[0123] Note: Common reaction conditions in Table 1: ML 0.33 g, solvent 30 mL.

[0124] As shown in Table 2, the efficiency of converting M5B into 5-ALA in the preparation methods of Examples 1 to 25 is as follows:

[0125]

[0126] Table 2

[0127] Note: Common reaction conditions in Table 2: amination: M5B 0.1 g, EA 10 mL, 40°C, 2 h; acid hydrolysis: M5P 0.1 g, HCl 10 mL, 110°C.

[0128] In summary, in Example 3 of the present invention, 0.33g of levulinic acid and its esterified derivatives are used as substrates, methanol and acetonitrile are mixed in a ratio of 1:1 as solvent, and 2.55g of copper bromide is used as a bromination reagent. Through ultrasonic assisted dissolution, 94% of M5B reaction liquid can be obtained by reacting at 50°C for 3h; after the obtained M5B reaction liquid is purified, 0.1g of M5B and KPI are taken in EA solvent, n(KPI):n(M5B)=1.8:1, and reacted at 40°C for 2h, and M5P with a yield of more than 97% can be obtained through condensation reflux experiment; M5P is purified, and then 5h of 5-aminolevulinic acid can be obtained by acid hydrolysis with HCl at 110°C. The method is simple and feasible, the bromination reagent is common and easy to obtain, and the reaction conditions are mild; the comprehensive yield of the product is more than 80%, and it has good industrialization potential.

Claims

1. A method for preparing 5-aminolevulinic acid by ultrasound-assisted stepwise steps, characterized in that: The following steps are involved: S1, taking the reaction raw material and the bromination reagent in a molar ratio of reaction raw material: bromination reagent = 1:3-5, then mixing the reaction raw material and the bromination reagent in a reactor filled with methanol and acetonitrile solvents, heating and condensing reflux reaction at 30-70° C. for 2-4 hours, and then cooling to room temperature to obtain a 5-bromolevulinic acid methyl ester reaction solution with a substrate concentration of 0.001-3 g / mL; S2, the molar ratio is 1:1~2.6 = 5-bromolevulinic acid methyl ester reaction solution: potassium phthalimide. Take 5-bromolevulinic acid methyl ester reaction solution and potassium phthalimide, then mix the 5-bromolevulinic acid methyl ester reaction solution and potassium phthalimide in a solvent, react at 30~70°C for 0.5~2.5h, then obtain 5-(phthalimide) levulinic acid methyl ester through a condensation reflux experiment, and then acidolyze with an acidolysis reagent for 3~7h to generate 5-aminolevulinic acid.

2. The method for preparing 5-aminolevulinic acid by ultrasound-assisted stepwise method according to claim 1, characterized in that: In S1, the reaction raw materials are levulinic acid and its esterified derivatives with a substrate concentration of 0.001-3 g / mL.

3. The method for preparing 5-aminolevulinic acid by ultrasound-assisted stepwise steps according to claim 1, characterized in that: In S1, the bromination reagent is at least one of HBr, CuBr2, FeBr3, NiBr2, and CoBr2.

4. The method for preparing 5-aminolevulinic acid by ultrasound-assisted stepwise method according to claim 1, characterized in that: In S2, the solvent is at least one of dioxane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.

5. The method for preparing 5-aminolevulinic acid by ultrasound-assisted stepwise method according to claim 1, characterized in that: In S2, the acidolysis reagent is at least one of hydrochloric acid, acetic acid, hydrofluoric acid, and trifluoromethanesulfonic acid.

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