A method for preparing a 5-aminolevulinic acid salt intermediate

Abstract

This invention relates to a method for preparing a 5-aminoketovalerate intermediate, belonging to the field of pharmaceutical compound synthesis. The technical points are as follows: A method for preparing a 5-aminoketovalerate intermediate includes: reacting a compound of formula (4) with a reaction solvent b and an oxidizing agent b to obtain a compound of formula (6). Then, the compound of formula (6) is purified and acidically hydrolyzed to remove the protecting group, or directly acidically hydrolyzed to remove the protecting group to obtain 5-aminoketovalerate. This invention uses environmentally friendly oxidizing agents, which can reduce costs while meeting the quality requirements of high-quality pharmaceutical raw materials, and also improve production efficiency, meeting the needs of large-scale industrial production.

Description

[0001] This invention is a divisional application, based on the invention application with application number 2020105086409, application date June 6, 2020, entitled "A method for preparing a 5-aminoketovalerate salt intermediate". Technical Field

[0002] This invention relates to the field of pharmaceutical compound synthesis, and more specifically, to a method for preparing a 5-aminoketovalerate intermediate. Background Technology

[0003] Photodynamic therapy (PDT) originated in the 1970s and has gradually become one of the basic methods for treating tumors in recent years due to the development and progress of photosensitive substances. 5-Aminolevulinic acid hydrochloride is the hydrochloride salt of the new generation photodynamic therapy drug 5-aminolevulinic acid (5-ALA), and is used clinically to treat actinic keratosis (AK).

[0004] Although the structure of 5-aminolevulinic acid salt is simple, its synthesis is quite difficult, especially the process for industrial-scale production. The most relevant existing technologies are: 1. Using furanylmethylamine as raw material, phthalamide oxidation, photo-oxidation, reduction, and hydrolysis (EP607, 952):

[0005] 2. Using furanylamine as a raw material, reduction, phthalamide oxidation, ruthenium-catalyzed oxidation, and hydrolysis (EP483, 714):

[0006] The existing technical solutions described above have the following drawbacks: Both synthetic routes 1 and 2 use furfural as the starting material. Route 1 suffers from low yield in the photo-oxidation step, resulting in low purity of the intermediate and uncertain industrialization prospects. Route 2 uses an expensive ruthenium catalyst, leading to low yield in the key oxidation step and poor product quality. Furthermore, the intermediate requires two silica gel column purifications, increasing costs and making it another unsuitable option for industrialization. Currently, neither route has been reported to be a mature industrial-scale production method. Summary of the Invention

[0007] To address the shortcomings of existing technologies, one objective of this invention is to provide a method for preparing 5-aminoketovalerate intermediates. The method involves oxidation and other steps to obtain the 5-aminoketovalerate intermediate. The oxidation ring-opening step utilizes environmentally friendly potassium persulfate complex salt (Oxone), sodium persulfate, potassium persulfate, or hydrogen peroxide as the oxidizing agent, avoiding the use of expensive ruthenium catalysts. This method not only significantly reduces costs but also improves production efficiency. The reaction conditions are mild, and the overall process is environmentally friendly, meeting the needs of large-scale industrial production.

[0008] The above-mentioned objective of this invention is achieved through the following technical solution: A method for preparing a 5-aminoketovalerate intermediate, wherein the 5-aminoketovalerate intermediate is a compound of formula (6), comprising the following steps: The compound of formula (1) or formula (2) is oxidized in reaction solvent a at 2-70℃ under the action of oxidant a to obtain the compound of formula (5), and then hydrogenated to obtain the compound of formula (6). The chemical reaction equation is as follows: Wherein, R1 and R2 are C1-C2 alkyl groups, and R is hydrogen or C1-C4 alkyl group, respectively; The oxidant a is selected from one or more compounds selected from sodium persulfate, potassium persulfate, aqueous solution of hydrogen peroxide, potassium persulfate compound salt and sodium persulfate compound salt; The reaction solvent a is a mixed solution of organic solvent a and water; the water content in the reaction solvent a is 10-99 w / w%; the organic solvent a is a mixture of one or more compounds selected from acetone, butanone and dioxane.

[0009] By adopting the above technical solution, the compounds of formula (1) or formula (2) are oxidized by oxidants a, namely sodium persulfate, potassium persulfate, aqueous hydrogen peroxide solution, potassium persulfate monohydrate and sodium persulfate monohydrate, to obtain 5-aminoketovalerate intermediate. The oxidation step uses environmentally friendly oxidant a, which can not only effectively avoid the use of expensive ruthenium catalyst, but also the preparation method is simple, the reaction is mild, easy to operate, and the yield is high, which is suitable for large-scale industrial production.

[0010] The above oxidation process requires the presence of water. Based on the working principle of the oxidant (potassium persulfate complex salt), the presence of water helps the potassium persulfate complex salt release active oxygen [O], which can oxidize the compound of formula (1) or formula (2) to prepare the 5-aminolevulinate intermediate.

[0011] In a preferred embodiment, the present invention can be further configured such that the reaction temperature of the oxidation step is 20-50°C.

[0012] In a preferred embodiment, the present invention may be further configured such that the oxidant a is preferably a potassium persulfate complex salt.

[0013] By adopting the above technical solution, potassium persulfate complex salt (i.e., Oxone) has potassium persulfate as its active oxidizing component. Potassium persulfate is an inorganic peroxide that exists in the form of a triple salt combined with potassium bisulfate and potassium sulfate, hence the name potassium persulfate complex salt. The molecular formula of potassium persulfate complex salt is 2KHSO5·KHSO4K2SO4, and the molecular weight is 614.7. In addition, the above-mentioned potassium persulfate complex salt is a free-flowing white powdery solid that is easily soluble in water. It is usually relatively stable in the solid state, decomposes slowly, and does not produce harmful substances. Furthermore, after the above-mentioned potassium persulfate complex salt is dissolved in water, its active component potassium persulfate can release active oxygen [O], and through a catalytic chain reaction, it produces sulfuric acid free radicals, oxygen free radicals, and then hydroxyl free radicals (·OH) and other components. It can not only efficiently catalyze the oxidation of compounds of formula (1) or formula (2), but also has a wide range of functions such as killing microorganisms and decomposing organic pollutants, making it green and environmentally friendly.

[0014] The second objective of this invention is achieved through the following technical solution: A method for preparing a 5-aminoketovalerate intermediate, wherein the 5-aminoketovalerate intermediate is a compound of formula (6), comprising the following steps: The compound of formula (3) or formula (4) is oxidized in reaction solvent a at 2-70℃ under the action of oxidant a to obtain the compound of formula (6); The chemical reaction equation is as follows: Wherein, R1 and R2 are C1-C2 alkyl groups, and R is hydrogen or C1-C4 alkyl group, respectively; The oxidant a is selected from one or more compounds selected from sodium persulfate, potassium persulfate, aqueous solution of hydrogen peroxide, potassium persulfate compound salt and sodium persulfate compound salt; The reaction solvent a is a mixed solution of organic solvent a and water; the water content in the reaction solvent a is 10-99 w / w%; the organic solvent a is a mixture of one or more compounds selected from acetone, butanone and dioxane.

[0015] By adopting the above technical solution, the compound of formula (3) or formula (3) can also be oxidized using the same oxidant a to obtain the 5-aminoketovalerate intermediate. The oxidation step uses the environmentally friendly oxidant a, which not only effectively avoids the use of expensive ruthenium catalysts, but also the preparation method is simple, the reaction is mild, easy to operate, and has a high yield, making it suitable for large-scale industrial production.

[0016] In a preferred embodiment, the present invention may be further configured such that: the reaction solvent a is an aqueous solution of acetone, wherein the acetone content in the aqueous solution of acetone is 1-90 w / w%; the range of the reaction solvent a / compound of formula (1) or formula (2) or formula (3) or formula (4) is: 1.00-20 grams of reaction solvent a per gram of compound of formula (1) or formula (2) or formula (3) or formula (4).

[0017] In a preferred embodiment, the present invention may be further configured such that the acetone content in the aqueous acetone solution is 5-50% (w / w).

[0018] In a preferred embodiment, the present invention may be further configured such that the reaction solvent a / compound of formula (1) or formula (2) or formula (3) or formula (4) is preferably 2.00-10 grams of reaction solvent a per gram of compound (1) or formula (2) or formula (3) or formula (4).

[0019] By adopting the above technical solution, the acetone aqueous solution has good solubility for the oxidant, reactants and 5-aminoketovalerate intermediate, which enables the entire oxidation reaction to proceed in the forward direction and has a good reaction yield.

[0020] When the mass ratio of the reaction solvent to the reactants was determined experimentally to be 1:(1-20), the reaction yield was relatively high. When the optimized mass ratio of the reaction solvent to the reactants was determined experimentally to be 1:(2-10), the reaction yield was even higher.

[0021] In a preferred embodiment, the present invention may be further configured such that the oxidant a / compound of formula (1) or formula (2) or formula (3) or formula (4) ranges from 0.50 to 5.00 moles of oxidant a per mole of compound of formula (1) or formula (2) or formula (3) or formula (4).

[0022] In a preferred embodiment, the present invention may be further configured such that: when the oxidant a is selected from potassium persulfate complex salt, sodium persulfate complex salt, sodium persulfate or potassium persulfate, the range of the oxidant a / compound of formula (1) or formula (2) or formula (3) or formula (4) is: 0.50-2.00 moles of oxidant a per mole of compound of formula (1) or formula (2) or formula (3) or formula (4).

[0023] In a preferred embodiment, the present invention may be further configured such that: the oxidant a is selected from potassium persulfate complex salt, sodium persulfate complex salt, sodium persulfate or potassium persulfate; the range of the oxidant a / compound of formula (1) or formula (2) or formula (3) or formula (4) is: 0.55-1.60 moles of oxidant a per mole of compound of formula (1) or formula (2) or formula (3) or formula (4).

[0024] By adopting the above technical solution, the reaction yield is higher when the molar ratio of the effective component of oxidant a, potassium persulfate (KHSO5), to the reactants is determined to be 1:(1-2) through experiments; and the reaction yield is even higher when the molar ratio of the effective component of oxidant a, potassium persulfate (KHSO5), to the reactants is determined to be 1:(1.1-1.6) through experiments.

[0025] In a preferred embodiment, the present invention may be further configured such that when the oxidant a is an aqueous solution of hydrogen peroxide, the range of the oxidant a / compound of formula (1) or formula (2) or formula (3) or formula (4) is: 2.00-5.00 moles of oxidant a per mole of compound of formula (1) or formula (2) or formula (3) or formula (4).

[0026] In a preferred embodiment, the present invention may be further configured such that when the oxidant a is an aqueous solution of hydrogen peroxide, the range of the oxidant a / compound of formula (1) or formula (2) or formula (3) or formula (4) is: 2.00-4.00 moles of oxidant a per mole of compound of formula (1) or formula (2) or formula (3) or formula (4).

[0027] By adopting the above technical solution, the reaction yield is higher when the molar ratio of oxidant a (i.e., aqueous solution of hydrogen peroxide) to reactants is determined to be 1:(2-5) by experiments; and the reaction yield is even higher when the molar ratio of oxidant a (i.e., aqueous solution of hydrogen peroxide) to reactants is determined to be 1:(2-4) by experiments.

[0028] In a preferred embodiment, the present invention can be further configured such that the preparation steps of the compound of formula (2) are as follows: The compound of formula (1) is acidically hydrolyzed by acid catalyst i and organic solvent a to obtain the compound of formula (2); The chemical reaction equation is as follows: Wherein, R1 and R2 are C1-C2 alkyl groups; The acid catalyst i is selected from sulfuric acid or methanesulfonic acid.

[0029] By adopting the above technical solution, the compound of formula (1) is acidically hydrolyzed and ring-opened under the action of acid catalyst i and organic solvent a to obtain the compound of formula (2). At this time, the operator can prepare the compound of formula (2) from the compound of formula (1) as needed, which increases the ways to obtain the compound of formula (2).

[0030] In a preferred embodiment, the present invention can be further configured such that the preparation steps of the compound of formula (3) are as follows: The compound of formula (1) undergoes a hydrogenation reaction in reaction solvent d under the action of reducing agent d to obtain the compound of formula (3); the chemical reaction equation is as follows: Wherein, R1 and R2 are C1-C2 alkyl groups, and R is hydrogen or C1-C4 alkyl group, respectively; The reaction solvent d is selected from one or more of methanol, ethanol, n-propanol and isopropanol; The reducing agent d is selected from Ni / H2.

[0031] By adopting the above technical solution, the compound of formula (1) is hydrogenated and reduced in reaction solvent d under the action of reducing agent d to obtain the compound of formula (3). At this time, the operator can prepare the compound of formula (3) from the compound of formula (1) as needed, which increases the ways to obtain the compound of formula (3).

[0032] In a preferred embodiment, the present invention can be further configured such that the preparation steps of the compound of formula (4) are as follows: The compound of formula (3) is acidically hydrolyzed by acid catalyst ii and organic solvent a to obtain the compound of formula (4); The chemical reaction equation is as follows: Wherein, R1 and R2 are C1-C2 alkyl groups; The acid catalyst ii is selected from sulfuric acid or methanesulfonic acid.

[0033] By adopting the above technical solution, the compound of formula (3) is hydrolyzed and ring-opened in acid catalyst ii under the action of organic solvent a to obtain the compound of formula (4). At this time, the operator can prepare the compound of formula (1) to obtain the compound of formula (3) as needed, which increases the ways to obtain the compound of formula (4).

[0034] In a preferred embodiment, the present invention may be further configured such that: the purification method of the compound of formula (6) is solvent recrystallization, and the purification solvent is a mixed solution of organic solvent c and water; the organic solvent c is one or more of butyl acetate, ethyl acetate and methyl acetate; and the water content in the purification solvent is 5-90 w / w%.

[0035] In the recrystallization step, the range of the purification solvent / compound of formula (6) is: 1.00-50 grams of purification solvent per gram of compound of formula (6).

[0036] By adopting the above technical solution, aqueous solutions of butyl acetate, ethyl acetate, and methyl acetate are common purification solvents used for recrystallization. Heating has a high effect on dissolving the product, and cooling allows the product to recrystallize in the solution. Through the above process of dissolution and re-precipitation of solids, impurities that were originally coated by solids can be better dispersed and dissolved in the above purification solution, thereby achieving the effect of rapid product purification.

[0037] The presence of water increases the conditions for solid precipitation. Organic compounds are generally insoluble in water, but readily soluble in organic solvents such as butyl acetate, ethyl acetate, and methyl acetate. By controlling the ratio of butyl acetate, ethyl acetate, methyl acetate, and water, and by detecting the melting point of the product, the solubility of the product in the purification solvent can be increased by raising the temperature (boiling the solution), while the solubility of the product in the purification solvent can be decreased by cooling and lowering the temperature (immersing in cooling water). This achieves the purpose of recrystallization and improves the purity of the product.

[0038] In a preferred embodiment, the present invention may be further configured such that the range of the purification solvent / compound of formula (6) is preferably 3.00-10 grams of purification solvent per gram of compound (6).

[0039] By adopting the above technical solution, the amount of purification solvent needs to be varied according to the mass change of the compound in formula (6). By optimizing the amount of purification solvent, the recrystallization efficiency can be effectively improved, thereby effectively improving the purity of the product.

[0040] In a preferred embodiment, the present invention may be further configured such that the purification solvent is an aqueous solution of ethyl acetate, wherein the ethyl acetate content in the aqueous solution is 95-10 w / w.

[0041] In a preferred embodiment, the present invention may be further configured such that the purification solvent is an aqueous solution of ethyl acetate, wherein the ethyl acetate content in the aqueous solution is 40-80 w / w.

[0042] By adopting the above technical solution, ethyl acetate, a colorless and transparent organic liquid with the molecular formula C4H8O2, is miscible with chloroform, ethanol, acetone, and diethyl ether, soluble in water (10% ml / ml), and has a boiling point of 77℃. Acetone has a boiling point of 56.53℃, and water has a boiling point of 100℃. Therefore, using an aqueous solution of ethyl acetate as a purification solvent, mixed with acetone and water, and controlling the dosage, can effectively achieve good recrystallization and improve the purity of the product.

[0043] The above-mentioned third objective of this invention is achieved through the following technical solution: The application of the 5-aminolevulinate intermediate prepared in this invention in the synthesis of 5-aminolevulinate.

[0044] The specific synthesis methods include: after purification of the compound of formula (6), the protecting group is removed by acidic hydrolysis, or the protecting group is removed by direct acidic hydrolysis to obtain 5-aminoketovalerate salt.

[0045] By adopting the above technical solution, the compound of formula (6) is purified and then acidically hydrolyzed to remove the protecting group, or directly acidically hydrolyzed to remove the protecting group to obtain the product 5-aminoketovalerate salt. The key difference between the synthesis method of this application and the synthesis method mentioned in the background art is that the intermediates of 5-aminoketovalerate salt prepared in this application are all solids and are easy to crystallize and purify. Therefore, the synthesized product 5-aminoketovalerate salt has high quality, and the yield and purity of the product are high. At the same time, it is environmentally friendly and conducive to industrial production.

[0046] In summary, the present invention has the following beneficial effects: 1. In the oxidation reaction of this invention, the oxidant used is sodium persulfate, potassium persulfate, potassium persulfate monopersulfate composite salt, sodium persulfate monopersulfate composite salt, or hydrogen peroxide aqueous solution, which avoids the use of expensive ruthenium catalyst, the reaction conditions are mild, environmentally friendly, the yield is high, the raw materials are simple and readily available, which is conducive to industrial production.

[0047] 2. The intermediate products of this invention are mostly solid compounds, which are easy to crystallize and purify; therefore, the synthesized product 5-aminolevulinate has high quality. It is not only simple and convenient to operate, but also has a high yield and purity, which plays a decisive role in the preparation of pharmaceutical-grade high-quality 5-aminolevulinate.

[0048] 3. This invention not only enables the final 5-aminolevulinate salt product to have a quality far exceeding the requirements of the United States Pharmacopeia standard, with a purity of over 99.99%, which greatly satisfies the pursuit of high-quality 5-aminolevulinate salt raw materials, but also significantly reduces costs and improves production efficiency, meeting the needs of large-scale industrial production.

[0049] 4. The study also found that the aqueous solution of fatty acid esters has a very efficient purification effect on the compound of formula (6), and its purity can be increased from 82% to more than 99%, which greatly meets the needs of producing high-quality pharmaceutical grade 5-aminolevulinic acid salt.

[0050] 5. The purification method for the compound in formula (6) is solvent recrystallization. The purification solvent is a mixed solution composed of two of butyl acetate, ethyl acetate, methyl acetate and water. It is simple and efficient. Detailed Implementation

[0051] The present invention will be further described in detail below with reference to various embodiments.

[0052] I. Test Conditions (I) Experimental Materials Furfurylamine (Shandong Yuexing Chemical Co., Ltd.), potassium persulfate monoperoxide compound salt (Oxone, Lianyungang Xinjiang Environmental Protection Materials Co., Ltd.), 30% hydrogen peroxide (Sinopharm Chemical Reagent Co., Ltd.), anhydrous ethanol (Taicang Xintai Alcohol Co., Ltd.), phthalic anhydride (Aekyung Petrochemical Co., Ltd., South Korea); potassium acetate, sodium persulfate, potassium persulfate (Sinopharm Chemical Reagent Co., Ltd.); methanol (Sinopharm Chemical Reagent Co., Ltd.), bromine (Jiangsu Ward Chemical Co., Ltd.), concentrated sulfuric acid (Shanghai Jingteng Chemical Co., Ltd.), concentrated hydrochloric acid (Sinopharm Chemical Reagent Co., Ltd.), acetone (Sinopharm Gaoqiao Branch), ethyl acetate (Shanghai Wujing Chemical Plant), Raney nickel (Xinyi Jintong General Chemical Co., Ltd.), platinum dioxide (Nanjing Chemical Reagent Co., Ltd.).

[0053] (II) Experimental Instruments (III) Chromatographic Detection Methods Liquid chromatography column: octadecylsilane-bonded silica gel is used as the packing material.

[0054] Mobile phase: Acetonitrile-ion-pair buffer = 18:82 (5-aminoketovalerate) or 28:72 (5-phthalimide levulinic acid).

[0055] Ion-pair buffer: Dissolve 1.15g ammonium dihydrogen phosphate and 2.16g sodium octane sulfonate in 800mL of water, adjust the pH to 2.0 with phosphoric acid, and dilute with water to 1000mL.

[0056] Detection wavelength: 205nm (5-aminoketovalerate) or 220nm (5-phthalimide levulinic acid).

[0057] Sample concentration: Dissolve and dilute in the mobile phase to 0.5 mg / 1 ml (5-aminoketovalerate) or 1.0 mg / 1 ml (5-phthalimide levulinic acid). Injection volume: 20 μl.

[0058] (iv) Raw material preparation 1. Preparation of N-phthaliminomethylfuran 500 g of furfurylamine (5.15 mol) was added to a three-necked flask, and 763 g of phthalic anhydride (5.15 mol) was slowly added with stirring. The mixture was heated and distilled for 3 hours to remove water. The reaction solution was cooled to obtain a light brownish-yellow crystalline solid. The solid was recrystallized with an appropriate amount of methanol, filtered, and dried to obtain 1146 g of N-phthaliminomethylfuran, mp 120℃, yield 98%.

[0059] 2. Preparation of cis,trans-2-phthaliminomethyl-2,5-dialkoxydihydrofuran In a three-necked flask, 113.6 g (0.50 mol) of N-phthaliminomethylfuran, 100 g of potassium acetate, and 3000 mL of methanol were added sequentially. After stirring to dissolve, 25 mL of liquid bromine (0.50 mol) was slowly added dropwise. After stirring for 1 hour, the methanol was recovered by heating and distillation. The mixture was then cooled to crystallize, filtered, washed with water, and dried under vacuum to obtain 130.2 g of cis,trans-2-phthaliminomethyl-2,5-dialkoxydihydrofuran, with a yield of 90%.

[0060] 3. Preparation of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran In a three-necked flask, 113.6 g (0.50 mol) of N-phthaliminomethylfuran, 100 g of potassium acetate, and 3000 mL of methanol were added sequentially. After stirring and dissolving, 25 mL of liquid bromine (0.50 mol) was slowly added dropwise. After stirring for 2 hours, the mixture was heated and distilled down to about 1400 mL. The inorganic salts were removed by filtration. The filtrate was added with the amount of catalyst to obtain Raney nickel. Hydrogen was passed through the filtrate until hydrogen absorption was complete, and the reaction was continued for 2 hours. After filtering off the Raney nickel, the methanol was recovered by heating and distillation. Water was added and the mixture was cooled to crystallize. The obtained solid was washed with water and dried under vacuum to obtain 137.6 g of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran, with a yield of 95%.

[0061] II. Examples and Comparative Examples Example 1 A method for preparing a 5-aminolevulinic acid salt intermediate includes the following steps: 99.0 g (0.34 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 700 ml of acetone by stirring, and then 140 ml of water was added. 4 g of 36% sulfuric acid was added, followed by the slow addition of 209 g (0.34 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 20 °C for 3 hours. After the reaction was completed, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washing liquid and filtrate were combined and concentrated under reduced pressure to remove the solvent. 400 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 87.0 g of 5-phthalimide levulinic acid, mp 163 °C, purity (HPLC, a / a%) 99.5%, yield 98.0% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0062] Its 1H NMR data are as follows: 1H NMR (δppmín CDCl3, 400MHZ): 2.61 (2H,t), 2.84 (2H,t), 4.57 (2H,s), 7.57-7.95 (Ar 4H,m).

[0063] Application of Example 1 Application Example 1: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 10 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 200 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 6.1 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0064] The proton NMR data are as follows: 1 HNMR (300MHz, D2O): δ2.59 (t, J = 5.9 Hz, 2H, CH2), 2.77 (t, J = 6.0 Hz, 2H, CH2), 4.04 (s, 2H, CH2).

[0065] Comparative Example 1 A method for preparing a 5-aminolevulinic acid salt intermediate includes the following steps: 46.7 g (0.15 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a three-necked flask and dissolved in 600 ml of acetone. After cooling to 0 °C, a mixed solution of 118 g of chromium trioxide, 88 ml of concentrated sulfuric acid, and 588 ml of water was slowly added dropwise. After the addition, the mixture was stirred for 2 hours. After the reaction was completed, the acetone was removed by vacuum distillation. The mixture was filtered, and the filter cake was washed with water and dried to obtain 25.1 g of 5-phthalimide levulinic acid, with a yield of 60% (based on N-phthaliminomethylfuran).

[0066] Application of Comparative Example 1 Application Example 1-1: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 20 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 400 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation, and the residue was recrystallized from acetone to obtain 9.3 g of solid. Based on the 1H NMR data, the solid was identified as 5-aminoketolate valerate, with a yield of 75% (based on 5-phthalimide levulinic acid); mp: 148℃.

[0067] The proton NMR data are as follows: 1 HNMR (300MHz, D2O): δ2.59 (t, J = 5.9 Hz, 2H, CH2), 2.77 (t, J = 6.0 Hz, 2H, CH2), 4.04 (s, 2H, CH2).

[0068] Example 2 A method for preparing a 5-aminolevulinic acid salt intermediate includes the following steps: Take 130.2 g (0.25 mol) of cis,v-2-phthaliminomethyl-2,5-dialkoxydihydrofuran, add Raney nickel as catalyst, and react with hydrogen until hydrogen absorption is complete, then react for another 2 hours. After filtering off Raney nickel, heat and distill to recover methanol. Add 500 ml of acetone, stir to dissolve, and then add 100 ml of water. Add 3 g of 36% sulfuric acid, and then slowly add 153.7 g (0.25 mol) of potassium persulfate complex salt (Oxone). Stir at 15 °C for 3 hours. After the reaction is complete, filter out the inorganic salt, wash the filter cake with acetone, combine the washing liquid and filtrate, concentrate under reduced pressure to remove the solvent, add 300 ml of water, stir for half an hour, filter, wash the filter cake with water, recrystallize with ethyl acetate, and dry under vacuum. 58.8 g of 5-phthaliminomethylpropionic acid was obtained, mp 162 °C, purity (HPLC, a / a%) 99.99%, yield 90% (based on N-phthaliminomethylfuran).

[0069] Application of Example 2 Application Example 2: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 20 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 400 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 11.9 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 96% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0070] The proton NMR data are as follows: 1 HNMR (300MHz, D2O) δ: 2.59 (t, J = 5.9 Hz, 2H, CH2), 2.77 (t, J = 6.0 Hz, 2H, CH2), 4.04 (s, 2H, CH2).

[0071] Comparative Example 2 A method for preparing a 5-aminolevulinic acid salt intermediate includes the following steps: In a three-necked flask, 56.8 g (0.25 mol) of N-phthaliminomethylfuran, 50 g of potassium acetate, and 1500 mL of methanol were added sequentially. After stirring and dissolving, 12.5 mL of liquid bromine (0.25 mol) was slowly added dropwise. After stirring for 2 hours, the mixture was heated and distilled down to about 700 mL. The inorganic salts were removed by filtration. 1.5 g of platinum dioxide was added to the filtrate, and hydrogen gas was passed through under normal pressure with stirring until the reaction was complete. After filtering the catalyst, methanol was distilled under reduced pressure at 30 °C. After dissolving in 600 mL of acetone, the mixture was cooled to 0 °C, and a mixed solution of 118 g of chromium trioxide, 88 mL of concentrated sulfuric acid, and 588 mL of water was slowly added dropwise. After adding the solution, stirring was continued for 2 hours. After the reaction was completed, acetone was removed by distillation under reduced pressure. The mixture was filtered, and the filter cake was washed with water and dried to obtain 28.6 g of 5-phthaliminomethylfuran with a purity (HPLC, a / a%) of 90.3% and a yield of 39.55% (based on N-phthaliminomethylfuran).

[0072] Application of Comparative Example 2 Application Example 1-2: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 20 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 400 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation, and the residue was recrystallized from acetone to obtain 9.4 g of solid. Based on the 1H NMR data, the solid was identified as 5-aminoketolate valerate, with a yield of 76% (based on 5-phthalimide levulinic acid); mp: 148℃.

[0073] The proton NMR data are as follows: 1 HNMR (300MHz, D2O): δ2.59 (t, J = 5.9 Hz, 2H, CH2), 2.77 (t, J = 6.0 Hz, 2H, CH2), 4.04 (s, 2H, CH2).

[0074] Example 3 A method for preparing a 5-aminolevulinic acid salt intermediate differs from that in Example 1 in that: Take 65.1 g (0.25 mol) of cis,trans-2-phthaliminomethyl-2,5-dialkoxydihydrofuran, remove the solvent by heating and distillation, dissolve in 500 ml of acetone by stirring, then add 100 ml of water; add 3 g 153.7 g (0.25 mol) of potassium persulfate complex salt (Oxone) was slowly added after 36% sulfuric acid, and stirred at 25 °C for 3 hours. After the reaction was completed, the inorganic salt was filtered out, the filter cake was washed with acetone, and the washing liquid and filtrate were combined and concentrated under reduced pressure to remove the solvent. 1500 mL of methanol was added and stirred to dissolve, and then Raney nickel was added as a catalyst amount. Hydrogen was passed through the filter until the hydrogenation reaction was completed. After filtering out Raney nickel, the solvent was removed by heating and distillation. 300 mL of water was added, and the mixture was stirred for half an hour and then filtered. The filter cake was washed with water and dried under vacuum. 60.1 g of 5-phthalimide levulinic acid was obtained, mp 163 °C, purity (HPLC, a / a%) 99.5%, yield 92% (calculated as N-phthalimide methyl furan).

[0075] Application of Example 3 Application Example 3: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 10.0 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 200 ml of 6N hydrochloric acid by heating and refluxed for 6 hours. The mixture was then decolorized with activated carbon, filtered, and subjected to vacuum distillation to remove all water. The residue was recrystallized from acetone to obtain 5.95 g of solid (mp: 149℃, purity (HPLC, a / a%)) 99.9%. Based on the 1H NMR data, the solid was identified as 5-aminoketolate valerate, with a yield of 96% (based on 5-phthalimide levulinic acid).

[0076] Example 4 A method for preparing a 5-aminolevulinic acid salt intermediate includes the following steps: 43.7 g (0.15 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, and 300 ml of acetone was added and stirred to dissolve. Then, 30 g of 36% sulfuric acid was added, and the mixture was stirred at 20 °C for 24 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. 200 ml of water was added, and the mixture was stirred for 2 hours. The mixture was then filtered, the filter cake was washed with water, and then dried under vacuum to obtain 36 g of 5-phthalimide acetylacetal, with a yield of 98%.

[0077] 12.3 g (0.05 mol) of 5-phthalimide acetylpropionaldehyde was added to a reaction flask, and 90 ml of acetone was added and stirred to dissolve it. Then, 0.5 g of 36% sulfuric acid was added, followed by the slow addition of 30.8 g (0.05 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 20 °C for 3 hours. After the reaction was completed, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washing liquid and filtrate were combined and concentrated under reduced pressure to remove the solvent. 80 ml of water was added, stirred, and then filtered. The filter cake was washed with water and dried under vacuum to obtain 12.4 g of 5-phthalimide acetylpropionic acid with a purity (HPLC, a / a%) of 99.5% and a yield of 95% (based on 5-phthalimide acetylpropionaldehyde).

[0078] Application of Example 4 Application Example 4: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to give 1.22 g of solid (mp: 149℃, purity (HPLC, a / a%)) 99.9%. Based on the 1H NMR data, the solid was identified as 5-aminoketolate valerate, with a yield of 95.1% (based on 5-phthalimide levulinic acid).

[0079] Example 5 A method for preparing a 5-aminolevulinic acid salt intermediate includes the following steps: 43.4 g (0.15 mol) of cis,v-2-phthaliminomethyl-2,5-dialkoxydihydrofuran was added to a reaction flask, and 300 ml of acetone was added and stirred to dissolve. Then, 30 g of 36% sulfuric acid was added, and the mixture was stirred at 20 °C for 24 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. 200 ml of water was added, and the mixture was stirred for 2 hours. The mixture was then filtered, the filter cake was washed with water, and then dried under vacuum to obtain 35 g of 5-phthaliminoacetylacetal, with a yield of 96%.

[0080] 12.2 g (0.05 mol) of 5-phthalimide acetopropionic acid was added to a reaction flask, and 90 ml of acetone was added and stirred to dissolve it. Then, 0.5 g of 36% sulfuric acid was added, followed by the slow addition of 30.8 g (0.05 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 20 °C for 3 hours. After the reaction was completed, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washing liquid and filtrate were combined and concentrated under reduced pressure to remove the solvent. 80 ml of water was added, stirred, and then filtered. The filter cake was washed with water and dried under vacuum to obtain 12.5 g of 5-phthalimide acetopropionic acid, with a yield of 96% (based on 5-phthalimide acetopropionic acid).

[0081] 9.7 g (0.04 mol) of 5-phthalimide acetopropionic acid was added to a hydrogenation reactor, and 200 mL of methanol was added and stirred to dissolve it. Then, a catalyst amount of Raney nickel (about 1 g) was added, and the reaction was carried out with hydrogen until the hydrogenation reaction was completed. After filtering off the Raney nickel, the solvent was removed by heating and distillation. 60 mL of water was added, and the mixture was stirred for half an hour and then filtered. The filter cake was washed with water and dried under vacuum. 10.1 g of 5-phthalimide acetopropionic acid was obtained, with a purity (HPLC, a / a%) of 99.5% and a yield of 98% (calculated as 5-phthalimide acetopropionic acid).

[0082] Application of Example 5 Application Example 5: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and refluxed for 6 hours. The mixture was then decolorized with activated carbon, filtered, and subjected to vacuum distillation to remove all water. The residue was recrystallized from acetone to give 1.21 g of solid (mp: 149℃, purity (HPLC, a / a%)) 99.9%. Based on the 1H NMR data, the solid was identified as 5-aminoketolate valerate, with a yield of 94.3% (based on 5-phthalimide levulinic acid).

[0083] Example 6 A method for preparing a 5-aminoketovalerate intermediate differs from Example 4 in that a purification step is added after Example 4.

[0084] 12.3 g (0.05 mol) of 5-phthalimide acetylpropionaldehyde obtained in Example 4 was added to a reaction flask, 90 ml of acetone was added and stirred to dissolve, 0.5 g of 36% sulfuric acid was added, and 22.7 g (0.20 mol) of 30% hydrogen peroxide was slowly added dropwise. The mixture was stirred at 30 °C for 6 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, 80 ml of water was added, the mixture was stirred and filtered, and the filter cake was recrystallized from ethyl acetate and water and dried under vacuum to obtain 12.8 g of 5-phthalimide acetylpropionic acid, mp 164 °C, purity (HPLC, a / a%) 99.9%, yield 98% (based on 5-phthalimide acetylpropionaldehyde).

[0085] Application of Example 6 Application Example 6: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and refluxed for 6 hours. The mixture was then decolorized with activated carbon, filtered, and subjected to vacuum distillation to remove all water. The residue was recrystallized from acetone to give 1.23 g of solid (mp: 149℃, purity (HPLC, a / a%)) 99.9%. Based on the 1H NMR data, the solid was identified as 5-aminoketolate valerate, with a yield of 96.1% (based on 5-phthalimide levulinic acid).

[0086] Example 7 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that a purification step is added after Example 1.

[0087] 10.0 g of 5-phthalimide levulinic acid prepared according to Example 1 was added to a reaction flask, along with 40 g of ethyl acetate and 20 g of water. The mixture was stirred and heated to reflux until dissolved, then slowly cooled to 10 °C and stirred for 6 hours. The mixture was filtered, washed with ethyl acetate, and dried under vacuum to obtain 9.8 g of 5-phthalimide levulinic acid with a purity (HPLC, a / a%) of 99.99% and a yield of 98%.

[0088] Application of Example 7 Application Example 7: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 5g of purified 5-phthalimide levulinic acid was dissolved in 50ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The solution was decolorized by activated carbon and filtered. The solution was then distilled under reduced pressure to remove all water. The residue was recrystallized from acetone to give 3.07g of 5-aminoketolate valerate, mp: 150℃, purity (HPLC, a / a%) 99.98%, yield 96% (based on 5-phthalimide levulinic acid).

[0089] Example 8 A method for preparing a 5-aminoketovalerate intermediate, which differs from Comparative Example 1 in that a purification step is added after Comparative Example 1.

[0090] 10 g of 5-phthalimide levulinic acid (purity 93.2%) prepared according to Comparative Example 1 was added to a reaction flask, along with 40 g of ethyl acetate and 20 g of water. The mixture was stirred and heated to reflux until dissolved, then slowly cooled to 10 °C and stirred for 6 hours. The mixture was filtered, washed with ethyl acetate, and dried under vacuum to obtain 8.85 g of 5-phthalimide levulinic acid with a purity (HPLC, a / a%) of 99.95% and a yield of 95% (calculated based on the pure yield of 5-phthalimide levulinic acid).

[0091] Application of Example 8 Application Example 8: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 5g of the purified 5-phthalimide levulinic acid was dissolved in 50ml of 6N hydrochloric acid by heating and refluxed for 6 hours. After decolorization with activated carbon and filtration, the product was removed by vacuum distillation to remove all water. The residue was recrystallized with acetone to give 3.04g of 5-aminoketolate valerate, mp: 150℃, purity (HPLC, a / a%) 99.96%, yield 95% (based on 5-phthalimide levulinic acid).

[0092] Example 9 A method for preparing a 5-aminoketovalerate intermediate, which differs from Comparative Example 2 in that a purification step is added after Comparative Example 2.

[0093] 10 g of 5-phthalimide levulinic acid (90.3% purity) prepared according to Comparative Example 2 was added to a reaction flask, along with 40 g of ethyl acetate and 20 g of water. The mixture was stirred and heated to reflux until dissolved, then slowly cooled to 10 °C and stirred for 6 hours. The mixture was filtered, washed with ethyl acetate, and dried under vacuum to obtain 8.49 g of 5-phthalimide levulinic acid, with a yield of 94% (calculated based on the purity of 5-phthalimide levulinic acid).

[0094] Application of Example 9 Application Example 9: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 5g of the purified 5-phthalimide levulinic acid was dissolved in 50ml of 6N hydrochloric acid by heating and refluxed for 6 hours. The mixture was then decolorized by activated carbon and filtered. The water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 3.07g of 5-aminoketolate valerate, with a yield of 96% (based on 5-phthalimide levulinic acid); mp: 150℃.

[0095] Example 10 A method for preparing a 5-aminoketovalerate intermediate differs from Example 6 in that a purification step is added after Example 6.

[0096] 200g of 5-phthalimide levulinic acid was prepared according to Example 6. 10g of the purified mother liquor was recovered and dried (purity 82.2%). 40g of ethyl acetate and 20g of water were added, and the mixture was stirred and heated to reflux until dissolved. The mixture was then slowly cooled to 10°C and stirred for 6 hours. After filtration, the mixture was washed with ethyl acetate and dried under vacuum to obtain 7.40g of 5-phthalimide levulinic acid, with a yield of 90% (calculated based on the purity of the recovered 5-phthalimide levulinic acid mother liquor).

[0097] Application of Example 10 Application Example 10: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 5g of the purified 5-phthalimide levulinic acid obtained above was dissolved in 50ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. After decolorization with activated carbon and filtration, the water was removed by vacuum distillation. The residue was recrystallized with acetone to obtain 3.04g of 5-aminoketolate salt, with a yield of 95% (based on 5-phthalimide levulinic acid); mp: 149℃.

[0098] Example 11 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that the oxidation temperature is different.

[0099] The specific operation includes the following steps: 4.95 g (0.017 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 35 ml of acetone, and then 7 ml of water was added. 0.2 g of 36% sulfuric acid was added, followed by the slow addition of 10.5 g (0.017 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washings and filtrate were combined and concentrated under reduced pressure to remove the solvent. 20 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 4.33 g of 5-phthalimide levulinic acid, mp 163 °C, purity (HPLC, a / a%) 99.5%, yield 97.5% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0100] Application of Example 11 Application Example 11: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 1.23 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95.9% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0101] Example 12 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that the oxidation temperature is different.

[0102] The specific operation includes the following steps: 4.95 g (0.017 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 35 ml of acetone, and then 7 ml of water was added. 0.2 g of 36% sulfuric acid was added, followed by the slow addition of 10.5 g (0.017 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 5°C until the reaction was complete. After the reaction was complete, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washings and filtrate were combined and concentrated under reduced pressure to remove the solvent. 20 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 4.30 g of 5-phthalimide levulinic acid, mp 163°C, purity (HPLC, a / a%) 99.5%, yield 96.9% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0103] Application of Example 12 Application Example 12: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 1.22 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95.1% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0104] Example 13 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that the oxidation temperature is different.

[0105] The specific operation includes the following steps: 4.95 g (0.017 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 35 ml of acetone, and then 7 ml of water was added. 0.2 g of 36% sulfuric acid was added, followed by the slow addition of 10.5 g (0.017 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 65 °C until the reaction was complete. After the reaction was completed, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washing liquid and filtrate were combined and concentrated under reduced pressure to remove the solvent. 20 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 4.34 g of 5-phthalimide levulinic acid, mp 163 °C, purity (HPLC, a / a%) 99.5%, yield 97.8% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0106] Application of Example 13 Application Example 13: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 1.23 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95.9% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0107] Example 14 A method for preparing a 5-aminoketovalerate intermediate, which differs from Example 1 in that the oxidant a is sodium persulfate.

[0108] 4.95 g (0.017 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 35 ml of acetone by stirring, and then 7 ml of water was added. 0.5 g of 36% sulfuric acid was added, followed by the slow addition of 4.76 g (0.020 mol) of sodium persulfate. The mixture was stirred at 50 °C until the reaction was complete. After the reaction was complete, the inorganic salts were filtered out, and the filter cake was washed with acetone. The washings and filtrate were combined and concentrated under reduced pressure to remove the solvent. 20 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 4.15 g of 5-phthalimide levulinic acid, mp 163 °C, purity (HPLC, a / a%) 99.5%, yield 93.5% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0109] Application of Example 14 Application Example 14: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation, and the residue was recrystallized from acetone to obtain 1.24 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 96.6% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0110] Example 15 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that both oxidant a and oxidant b are aqueous solutions of hydrogen peroxide.

[0111] 4.95 g (0.017 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 35 ml of acetone by stirring, and then 7 ml of water was added. 0.5 g of 36% sulfuric acid was added, followed by the slow addition of 5.78 g (0.051 mol) of 30% hydrogen peroxide aqueous solution. The mixture was stirred at 20°C until the reaction was complete. The solvent was removed by vacuum concentration, 20 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 4.23 g of 5-phthalimide levulinic acid, mp 163°C, purity (HPLC, a / a%) 99.5%, yield 95.3% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0112] Application of Example 15 Application Example 15: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 1.23 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95.9% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0113] Example 16 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that: oxidant a is a potassium persulfate complex salt, and oxidant b is an aqueous solution of hydrogen peroxide.

[0114] 4.95 g (0.017 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 35 ml of acetone, and then 7 ml of water was added. 0.5 g of 36% sulfuric acid was added, followed by the slow addition of 3.69 g (0.006 mol) of potassium persulfate (Oxone). The mixture was stirred at 25°C for 3 hours, and then 1.7 g (0.015 mol) of 30% hydrogen peroxide aqueous solution was added dropwise. The mixture was stirred at 25°C until the reaction was complete. After the reaction was complete, the inorganic salts were filtered out, and the filter cake was washed with acetone. The washings and filtrate were combined and concentrated under reduced pressure to remove the solvent. 20 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 4.24 g of 5-phthalimide levulinic acid, mp 163°C, purity (HPLC, a / a%) 99.5%, yield 95.5% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0115] Application of Example 16 Application Example 16: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 2.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 40 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation. The residue was recrystallized from acetone to obtain 1.22 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95.1% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0116] Example 17 A method for preparing a 5-aminoketovalerate intermediate differs from Example 1 in that the solvent used in the oxidation reaction is different.

[0117] 9.9 g (0.034 mol) of 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran was added to a reaction flask, dissolved in 70 ml of dioxane by stirring, and then 14 ml of water was added. 0.4 g of 36% sulfuric acid was added, followed by the slow addition of 21 g (0.034 mol) of potassium persulfate complex salt (Oxone). The mixture was stirred at 20 °C for 3 hours. After the reaction was complete, the inorganic salt was filtered out, and the filter cake was washed with acetone. The washings and filtrate were combined and concentrated under reduced pressure to remove the solvent. 40 ml of water was added, and the mixture was stirred for half an hour before filtration. The filter cake was washed with water and then dried under vacuum to obtain 8.5 g of 5-phthalimide levulinic acid, mp 162 °C, purity (HPLC, a / a%) 99.5%, yield 96.0% (based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran).

[0118] Application of Example 17 Application Example 17: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 1.0 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 20 ml of 6N hydrochloric acid by heating and then refluxed for 6 hours. The mixture was decolorized with activated carbon and filtered. Water was removed by vacuum distillation, and the residue was recrystallized from acetone to obtain 0.61 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 95% (based on 5-phthalimide levulinic acid); mp: 149℃, purity (HPLC, a / a%) 99.9%.

[0119] The proton NMR data are as follows: 1 HNMR (300MHz, D2O) δ: 2.59 (t, J = 5.9 Hz, 2H, CH2), 2.77 (t, J = 6.0 Hz, 2H, CH2), 4.04 (s, 2H, CH2).

[0120] Comparative Example 3 A method for preparing a 5-aminoketolate valerate intermediate differs from Example 1 in that: 10g of the purified mother liquor recovered from Example 9 (purity 82.2%) is taken, 30g of acetone and 10g of water are added, the mixture is stirred and heated to reflux until dissolved, and then slowly cooled to 10°C and stirred for 6 hours; the mixture is filtered, washed with acetone, and then vacuum dried to obtain 7.23g of 5-phthalimide levulinic acid with a purity (HPLC, a / a%) of 85.2% and a yield of 75% (calculated based on the pure yield of 5-phthalimide levulinic acid).

[0121] Application of Comparative Example 3 Application Examples 1-3: A method for synthesizing 5-aminolevulinic acid salt, comprising the following steps: 5 g of the purified 5-phthalimide levulinic acid (purity 85.25%) was dissolved in 50 ml of 6N hydrochloric acid by heating and refluxed for 6 hours. After decolorization with activated carbon and filtration, the water was removed by vacuum distillation. The residue was recrystallized with acetone to give 2.13 g of 5-aminoketolate valerate, yield 78% (based on 5-phthalimide levulinic acid); mp: 149℃.

[0122] Comparative Example 4 A method for preparing 5-aminoketovalerate salt, using furanylmethylamine as a raw material, involves phthalamide oxidation, photo-oxidation, reduction, and hydrolysis (EP607,952): In a three-necked flask equipped with an oxygen delivery tube, thermometer, and reflux condenser, 2.27 g (0.010 mol) of N-phthaliminomethylfuran was added, along with 100 ml of anhydrous pyridine and 7 mg of rose red. The reaction was carried out at 10–20 °C with oxygen flowing through at a rate of 20 ml / min for 5 hours. Simultaneously, the reaction solution was irradiated from the outside of the flask with a 12 W light source. After 7 hours, the photo-oxidation reaction was stopped, and the pyridine was removed by vacuum distillation to obtain 2.47 g of semi-crystalline product.

[0123] The 2.47 g semi-crystalline product obtained above was dissolved in 50 ml of methanol, hydrogenated with 250 mg of 5% palladium on carbon, filtered to remove the solvent by vacuum distillation, and 2.61 g of crystals were obtained.

[0124] The 2.47 g crystals obtained above were dissolved in 120 ml of 6N hydrochloric acid upon heating, and then refluxed for 5 hours. The mixture was decolorized with activated carbon, filtered, and subjected to vacuum distillation to remove all water. The residue was recrystallized from acetone to obtain 0.851 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate salt, with a yield of 51% (as N-phthaliminomethylfuran); mp: 148℃, purity (HPLC, a / a%) 96.9%.

[0125] The proton NMR data are as follows: 1 HNMR (300MHz, D2O) δ: 2.59 (t, J = 5.9 Hz, 2H, CH2), 2.77 (t, J = 6.0 Hz, 2H, CH2), 4.04 (s, 2H, CH2).

[0126] Comparative Example 5 A method for preparing 5-aminoketovalerate salt, using furanylmethylamine as a raw material, involves reduction, phthalamide oxidation, ruthenium-catalyzed oxidation, and hydrolysis (EP483,714): (1) Preparation of N-phthaliminomethyltetrahydrofuran 19.8 g (134 mmol) of phthalic anhydride was dissolved in 500 mL of chloroform, and 10 g (99 mmol) of tetrahydrofurfurylamide was added with stirring. The mixture was refluxed to remove all water. The reaction mixture was cooled and then poured into 300 mL of saturated sodium bicarbonate aqueous solution to separate the organic solvent layer. The aqueous layer was extracted twice with chloroform, and the extracts were combined and washed with sodium bicarbonate aqueous solution, then washed with water, and dried over anhydrous magnesium sulfate. The organic solvent layer was removed by vacuum distillation to obtain a crude product, which was purified by recrystallization in a mixed solvent of hexane and dichloromethane to give 21.8 g of N-phthaliminomethyltetrahydrofuran, in 95.2% yield (based on tetrahydrofurfurylamide).

[0127] (2) Preparation of 5-phthalimide levulinic acid In a reaction flask, 25 ml of carbon tetrachloride, 25 ml of acetonitrile, and 30 ml of water were added sequentially. Then, 5.0 g (220 mmol) of N-phthaliminomethyltetrahydrofuran prepared in step (1) above was added and stirred until dissolved. Next, 19 g (87 mmol) of sodium periodate and 0.10 g (2.2 mol%) of ruthenium chloride hydrate were added, and the mixture was stirred vigorously overnight at room temperature. After the reaction was complete, the insoluble matter was filtered off, and the filtrate was vacuum distilled to remove the solvent. The residue was dissolved in a mixed solution of chloroform and 1N hydrochloric acid aqueous solution, and then extracted with chloroform. The organic solvent layer extract was dried over anhydrous magnesium sulfate and the solvent was removed by vacuum distillation to obtain the residue. The residue was purified by silica gel column chromatography. Elution with eluent A (chloroform:methanol = 95:5 v / v) first yielded 5-phthalimide-1,4-pentanolide; then elution with eluent B (chloroform:methanol:formic acid = 95:4:1 v / v) yielded 5-phthalimide levulinic acid.

[0128] Thus, 1.5 g of 5-phthalimide-1,4-pentanolide was obtained in a yield of 28% (based on N-phthalimide-methyltetrahydrofuran); and 2.1 g of 5-phthalimide-levulinic acid (purity 90.23%) was obtained in a yield of 37% (based on N-phthalimide-methyltetrahydrofuran).

[0129] The chemical structure of 5-phthalimide-1,4-pentanolide is as follows: In a reaction flask, 2 ml of carbon tetrachloride, 10 ml of acetonitrile, and 3 ml of water were added sequentially. Then, 0.3 g (1.2 mmol) of 5-phthalimide-1,4-pentanolide prepared in the previous step was added, and the mixture was stirred until dissolved. Next, 2.5 g (12 mmol) of sodium periodate and 90 mg (30 mol%) of ruthenium chloride hydrate were added, and the mixture was stirred vigorously at 50 °C for 24 hours. After the reaction was complete, the insoluble matter was filtered off, and the filtrate was vacuum distilled to remove the solvent. The residue was dissolved in a mixture of chloroform and 1N hydrochloric acid aqueous solution, and then extracted with chloroform. The organic solvent layer extract was dried over anhydrous magnesium sulfate and the solvent was removed by vacuum distillation to obtain the residue. The residue was purified by silica gel column chromatography, eluted with eluent B (chloroform:methanol:formic acid = 95:4:1 v / v), to obtain 32 mg of 5-phthalimide levulinic acid (purity 90.20%), yield 10% (5-phthalimide-1,4-pentanolide), mp 160℃.

[0130] The overall yield of 5-phthalimide levulinic acid preparation was 34.2% (based on tetrahydrofurfurylamide). (3) Preparation of 5-aminolevulinate 1.00 g of 5-phthalimide levulinic acid obtained in the previous step was dissolved in 20 ml of 6N hydrochloric acid by heating and refluxed for 6 hours. The mixture was then decolorized with activated carbon, filtered, and subjected to vacuum distillation to remove all water. The residue was recrystallized from acetone to obtain 0.49 g of solid. Based on the 1H NMR spectroscopy data, the solid was identified as 5-aminoketolate valerate, with a yield of 76.4% (based on 5-phthalimide levulinic acid); mp: 146℃, purity (HPLC, a / a%) 96.5%.

[0131] III. Experimental Data Statistics and Analysis Table 1: Statistical data of experimental synthesis of aminolevulinic acid hydrochloride and its intermediates Note: *Percentage of peak area in high performance liquid chromatography. a Based on 2-phthaliminomethyl-2,5-dimethoxytetrahydrofuran, b Based on cis,trans-2-phthaliminomethyl-2,5-dialkoxydihydrofuran, c Based on N-phthaliminomethylfuran, d Based on 5-phthalimide levulinic acid, e Calculated as 5-phthalimide acetylacetal, f Calculated as tetrahydrofurfurylamine.

[0132] Table 2: Statistical Analysis of Purification Experimental Data for 5-Phenylimide Levylpropionic Acid Note: a Based on 100% purity of 5-phthalimide levulinic acid before purification, b Calculated as 5-phthalimide levulinic acid.

[0133] Experimental results: As can be seen from the experimental data in Tables 1 and 2, the yields of Examples 1-9 are all greater than those of Comparative Examples 1-3; the purity of Examples 1-9 is all greater than that of Comparative Examples 1-3.

[0134] As shown in Table 2, the purity of 5-phthalimide levulinic acid in Examples 6-9 increased from over 90.3% to over 99.95% after purification, demonstrating a significant improvement. Furthermore, the purity of the purified intermediate 5-phthalimide levulinic acid remained above 99.96% after the synthesis of 5-aminoketovalerate. In contrast, the purity of 5-phthalimide levulinic acid in Comparative Example 3, after purification, remained at 85.25% (below 90%); simultaneously, the purity of the synthesized 5-aminoketovalerate was only 78%, significantly lower than 90%.

[0135] The specific embodiments are merely illustrative of the present invention and are not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to these embodiments without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. A method for preparing a 5-aminolevulinate intermediate, wherein the 5-aminolevulinate intermediate is a compound of formula (6), characterized in that, Includes the following steps: The compound of formula (4) is oxidized in reaction solvent a at 2-70℃ under the action of oxidant a to obtain the compound of formula (6); The chemical reaction equation is as follows: Where R is hydrogen; The oxidant a is selected from one or more compounds selected from sodium persulfate, potassium persulfate, aqueous solution of hydrogen peroxide, potassium persulfate compound salt and sodium persulfate compound salt; The reaction solvent a is a mixed solution of organic solvent a and water; the water content in the reaction solvent a is 10-99 w / w %; the organic solvent a is a mixture of one or more compounds selected from acetone, butanone and dioxane.

2. The method for preparing a 5-aminolevulinic acid salt intermediate according to claim 1, characterized in that, The reaction solvent a is an aqueous solution of acetone, and the acetone content in the aqueous solution of acetone is 1-90 w / w %; the range of the reaction solvent a / compound of formula (4) is: 1.00-20 grams of reaction solvent a are selected per gram of compound of formula (4).

3. The method for preparing a 5-aminolevulinic acid salt intermediate according to claim 1, characterized in that, The range of compounds of the oxidant a / formula (4) is: 0.50-5.00 moles of oxidant a per mole of compound of formula (4).

4. The method for preparing a 5-aminolevulinic acid salt intermediate according to claim 3, characterized in that, When the oxidant a is selected from potassium persulfate complex salt, sodium persulfate complex salt, sodium persulfate or potassium persulfate, the range of compounds of the oxidant a / formula (4) is: 0.50-2.00 moles of oxidant a per mole of compound of formula (4).

5. A method for preparing a 5-aminolevulinic acid salt intermediate according to claim 3, characterized in that, When the oxidant a is an aqueous solution of hydrogen peroxide, the range of compounds of the oxidant a / formula (4) is: 2.00-5.00 moles of oxidant a per mole of compound of formula (4).

6. A method for preparing a 5-aminolevulinic acid salt intermediate according to claim 1, characterized in that, The preparation steps of the compound of formula (4) are as follows: The compound of formula (3) is acidically hydrolyzed by acid catalyst ii and organic solvent a to give the compound of formula (4); The chemical reaction equation is as follows: Wherein, R1 and R2 are C1-C2 alkyl groups, respectively; The acid catalyst ii is selected from sulfuric acid or methanesulfonic acid.

7. The method for preparing a 5-aminolevulinic acid salt intermediate according to claim 6, characterized in that, The purification method for the compound of formula (6) is solvent recrystallization, wherein the purification solvent is a mixed solution of organic solvent c and water; wherein the organic solvent c is one or more of butyl acetate, ethyl acetate and methyl acetate; and the water content in the purification solvent is 5-90 w / w%. In the recrystallization step, the range of the purification solvent / compound of formula (6) is: 1.00-50 grams of purification solvent per gram of compound of formula (6).

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