Purification method of 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone

Abstract

The invention discloses a method for purifying 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone, which comprises the following steps of: adding a catalyst and a catalyst, the purification method comprises the following steps: dissolving a 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone crude product, then adjusting the pH value to be alkaline, and crystallizing and separating out the 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone, thereby obtaining the purified 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone. According to the purification method, the content of oxidation impurities in the product is remarkably reduced, and meanwhile, the purity of the product 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone can be improved, so that the product meets medicinal requirements.

Description

Technical Field

[0001] This invention belongs to the technical field of drug preparation, specifically relating to a purification method for 3,4-dihydro-7-hydroxy-2(1H)-quinolinone. Background Technology

[0002] Schizophrenia is a highly disabling mental illness affecting at least 1% of the world's population. Its clinical features include positive symptoms (hallucinations, delusions), negative symptoms (emotional flattening, social dysfunction), and cognitive impairment. Currently available medications for schizophrenia include aripiprazole and brexpiprazole. Aripiprazole, a quinolone derivative, is a third-generation atypical antipsychotic and the first dopamine system stabilizer, showing significant efficacy for both positive and negative symptoms of schizophrenia. It was approved by the FDA in November 2002 for the treatment of schizophrenia and has shown significant improvement in these symptoms. Buripiperazole is a novel drug with a multi-target mechanism of action for the treatment of mental disorders. In addition to its main dopamine D2 receptor partial agonist activity, it also has D3 receptor partial agonist activity, 5-HT1A receptor partial agonist activity, and 5-HT2A receptor partial antagonist activity. It is a new drug developed for multiple targets of monoamine neurotransmitters, which has both antipsychotic and antidepressant effects.

[0003] 3,4-Dihydro-7-hydroxy-2(1H)-quinolinone (HDQ, structural formula shown below) is an important intermediate in the synthesis of aripiprazole. Improving its quality and purity is crucial for ensuring that aripiprazole raw material meets pharmaceutical requirements. Current methods for preparing HDQ generate an oxidized impurity (impurity A, structural formula shown below). Impurity A has a highly similar structure to HDQ and is transferred to the finished aripiprazole product, forming impurity G (impurity II in the Chinese Pharmacopoeia standard, structure shown below). Both the United States Pharmacopeia and the Chinese Pharmacopoeia have specific requirements for this impurity, ≤0.10%. Therefore, if impurity A remains excessively high in HDQ, impurity G in the finished aripiprazole product will be substandard, failing to meet pharmaceutical requirements.

[0004]

[0005] Patent publication number CN112745262A discloses a method for preparing intermediate II (7-hydroxy-3,4-dihydro-1H-quinoline-2-one). After obtaining crude HDQ, it is dissolved in toluene and stirred. The reaction solution is then poured into ice water, precipitating a solid, which is then filtered to obtain the final product. Journal article "Synthesis of 7-hydroxy-3,4-dihydro-2(1H)-quinolineone and Isolation and Confirmation of Two Byproducts, Ge Haixia, Chinese Journal of Modern Applied Pharmacy" discloses recrystallization of the obtained crude HDQ with aqueous ethanol to purify the product. However, the above purification method is not effective in removing the oxidized impurity A from HDQ. The residual impurity A, after process transfer, forms impurity G exceeding 0.10% in the aripiprazole final product, failing to meet pharmaceutical requirements. Summary of the Invention

[0006] To address the aforementioned technical problems, the primary objective of this invention is to provide a purification method for 3,4-dihydro-7-hydroxy-2(1H)-quinolinone. This purification method can improve the purity of crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone while controlling the content of impurity A to be less than 0.10%, thus ensuring that the product meets pharmaceutical requirements.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention claims protection for a purification method of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, which involves dissolving crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, adjusting the pH to alkaline, crystallizing to obtain purified 3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

[0008] Compounds containing a phenolic structure are readily soluble in alkaline or sodium carbonate solutions due to the formation of readily soluble sodium salts. The inventors unexpectedly discovered that 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, after forming a basic salt under alkaline conditions, exhibits a high degree of precipitation in solution. Crystallization allows for effective separation of this salt from impurities in the crude product. The method provided by this invention significantly improves the purity of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, resulting in a significant reduction in the content of impurity A in the product, with the content of oxidized impurity A less than 0.10%, meeting pharmaceutical requirements.

[0009] Preferably, the alkaline pH is 7.5-13. More preferably, the alkaline pH is 9-11. More specifically, the alkaline pH can be 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, etc., or any range formed by the above values, such as 8-11, 9-11, 9-12, etc., and the present invention is not limited thereto.

[0010] Preferably, the pH is adjusted by adding an alkaline solution. The alkaline solution can be selected from those conventionally used in the art for forming basic salts. More specifically, in some embodiments, the alkaline solution is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. This preferred approach allows for higher yields and purity of the product HDQ.

[0011] Specifically, the mass concentration of the alkaline solution is 10-90%. More specifically, the mass concentration of the alkaline solution can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, etc. Those skilled in the art can conventionally adjust the concentration of the alkaline solution to obtain the corresponding alkaline conditions, and the present invention is not limited thereto.

[0012] Preferably, the crystallization is performed by cooling crystallization. The specific method for cooling crystallization can be selected from the cooling crystallization methods conventionally used in the art.

[0013] Preferably, the cooling endpoint temperature of the cooling crystallization is 0-10℃.

[0014] Preferably, the dissolution is selected from at least one of (a) to (c): (a) The solvent used for dissolution is selected from one or more solvents, such as water and alcohols; (b) The crude product is heated to 30-70℃ to dissolve; (c) The mass-to-volume ratio of crude product to solvent is ≤1g:1mL.

[0015] Preferably, the alcohol solvent is selected from alcohol solvents containing 1-6 carbon atoms. More preferably, the alcohol solvent is selected from at least one of methanol, ethanol, and propanol.

[0016] Preferably, the solvent used for dissolution is water.

[0017] Preferably, the crude product is dissolved by heating to 40-60°C. More preferably, the crude product is dissolved by heating to 45-55°C.

[0018] Preferably, the mass-to-volume ratio of crude product to solvent is 1 g: 1-10 mL. More preferably, the mass-to-volume ratio of crude product to solvent is 1 g: 1-5 mL. Most preferably, the mass-to-volume ratio of crude product to solvent is 1 g: 3 mL.

[0019] Preferably, after crystallization, the process further includes the following steps: filtering the precipitate, then continuing to dissolve it, adjusting the pH to acidic, crystallizing, filtering, and obtaining purified 3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

[0020] Preferably, at least one of the following (d) to (f): (d) The solvent used to dissolve the precipitate is selected from one or more of alcohol solvents, ketone solvents, and ether solvents; (e) The acid used to adjust the pH is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid; (f) Adjust the pH to 2-5.

[0021] More preferably, the alcohol solvent is selected from alcohol solvents containing 1-6 carbon atoms. More preferably, the alcohol solvent is selected from at least one of methanol, ethanol, and isopropanol.

[0022] More preferably, the ketone solvent can be a ketone solvent commonly used in the art, including but not limited to acetone.

[0023] More preferably, the ether solvent can be a conventionally used ether solvent in the art, including but not limited to tetrahydrofuran.

[0024] More preferably, the pH is adjusted to 2-3.

[0025] Specifically, in some embodiments, the content of impurity A in the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone is less than 0.10%. In some embodiments, the content of impurity A in the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone is ≥0.10%. In some embodiments, the content of impurity A in the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone is 0.10-1.0%. In some embodiments, the content of impurity A in the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone is 0.30-0.50%. More specifically, the content of impurity A in the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone can be ≥0.20%, ≥0.30%, ≥0.40%, ≥0.50%, ≥0.60%, ≥0.70%, ≥0.70%, ≥0.90%, ≥1.0%, ≥2.0%, ≥3.0%, ≥4.0%, ≥5.0%, etc., and the present invention is not limited thereto.

[0026] Specifically, the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone used in this invention can be prepared commercially available or by referring to existing preparation methods such as those published in patent publications CN112745262A and CN101302195A. Specifically, in some embodiments, the crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone provided by this invention can be prepared by the following method: Using carboxylic acid esters and chlorobenzene as reaction solvents and aluminum trichloride as catalyst, compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 60-120℃ to generate 3,4-dihydro-7-hydroxy-2(1H)-quinolinone; the reaction formula for the preparation method is shown below: .

[0027] Preferably, ethyl acetate and chlorobenzene are used as reaction solvents, or isopropyl acetate and chlorobenzene are used as reaction solvents.

[0028] Preferably, the volume ratio of carboxylic acid ester to chlorobenzene is 1:0.1-20. More preferably, the volume ratio of carboxylic acid ester to chlorobenzene is 1:3-7.

[0029] Preferably, compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 70-100°C.

[0030] Preferably, the molar ratio of the catalyst to compound 1a is 1:2.5-12. More preferably, the molar ratio of the catalyst to compound 1a is 1:3-7.

[0031] Preferably, the volume-to-mass ratio of the reaction solvent to compound 1a is 1-20 mL / g; more preferably, the volume-to-mass ratio of the reaction solvent to compound 1a is 4-10 mL / g.

[0032] Preferably, the reaction time for the intramolecular Friedel-Crafts alkylation reaction is 12-20 h.

[0033] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a purification method for 3,4-dihydro-7-hydroxy-2(1H)-quinolinone. This purification method effectively improves the purity of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, significantly reducing the content of impurity A in the product, with the content of oxidized impurity A being less than 0.10%, meeting pharmaceutical requirements. This purification method is suitable for industrial-scale production. Attached Figure Description

[0034] Figure 1 and Figure 2 The images shown are the proton and carbon spectra of the HDQ prepared in Example 1.

[0035] Figure 3 This is a schematic diagram showing the purity of HDQ prepared in Example 1.

[0036] Figure 4 This is a schematic diagram showing the purity of HDQ prepared in Example 2.

[0037] Figure 5 This is a schematic diagram showing the purity of HDQ prepared in Example 3.

[0038] Figure 6 This is a schematic diagram showing the purity of HDQ prepared in Comparative Example 1.

[0039] Figure 7 This is a schematic diagram illustrating the purity of HDQ prepared in Comparative Example 2.

[0040] Figure 8 This is a schematic diagram showing the purity of HDQ prepared in Comparative Example 3. Detailed Implementation

[0041] The present invention will be further described below with reference to the specification and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0042] Example 1 10.00 g of compound 1a and 60 mL of ethyl acetate / chlorobenzene solution (V / V = 1:6) were added to a 250 mL reaction flask. 28.05 g of aluminum trichloride was added while maintaining the temperature below 25 °C. The mixture was heated to 80 °C and reacted for 20 h, with TLC monitoring to ensure complete conversion of the starting material. The temperature was then lowered to 20–30 °C, and the mixture was quenched dropwise in 100 mL of 1% hydrochloric acid water pre-cooled to 0–10 °C. The organic solvent was removed by rotary evaporation, precipitating a solid. The solid was then cooled to 20–25 °C and filtered to obtain crude HDQ with a purity of 85.3% and impurity A content of 0.41%. The 1H and 1C spectra of HDQ are shown below. Figure 1 and Figure 2 As shown.

[0043] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50 °C, add dropwise 20% sodium hydroxide solution to adjust pH to 9, stir to dissolve, cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.77%, and the impurity A content is 0.09%.

[0044] The filtrate was dissolved in 50 mL of methanol at 25–30 °C, and a 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 8.5 g, with a yield of 85%, a purity of 99.70%, and an impurity A content of 0.03% (purity diagram shown). Figure 3 (As shown).

[0045] Example 2 10.00 g of compound 1a and 60 mL of ethyl acetate / chlorobenzene (V / V = 1:6) were added to a 250 mL reaction flask. 28.05 g of aluminum trichloride was added while maintaining the temperature below 25 °C. The mixture was then heated to 80 °C and refluxed for 20 h. The conversion of the starting material was monitored by TLC until complete. The mixture was cooled to 20–30 °C, and a solution of pre-cooled (0–10 °C) water was added dropwise. The solution was quenched in 100 mL of 1% hydrochloric acid water. The organic solvent was removed by rotary evaporation, and a solid precipitated. The solid was then cooled to 20–25 °C and filtered to obtain crude HDQ.

[0046] Add 35 mL of water to 10 g of crude HDQ raw material, heat to 55 °C, add 20% potassium hydroxide solution dropwise to adjust pH to 9, stir to dissolve, cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 97.6%, and the impurity A content is 0.07%.

[0047] The wet filtered product was dissolved in 50 mL of methanol at 25–30 °C, and a 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the product was dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 8.4 g, the yield was 84.4%, the purity was 99.54%, and the impurity A content was 0.04% (purity diagram shown). Figure 4 (As shown).

[0048] Example 3 1.0 kg of compound 1a and 6 L of ethyl acetate / chlorobenzene solution (V / V = 1:6) were added to a 250 mL reaction flask. 2.8 kg of aluminum trichloride (4 eq) was added while maintaining the temperature below 25 °C. The mixture was heated to 80 °C and reacted for 20 h, with TLC monitoring to ensure complete conversion of the starting materials. The mixture was then cooled to 20–30 °C, and the solution was added dropwise to a solution pre-cooled to 0–10 °C and quenched in 10 L of 1% hydrochloric acid water. The organic solvent was removed by rotary evaporation, and a solid precipitated. The solid was then cooled to 20–25 °C and filtered to obtain 820 g of crude HDQ with a purity of 86.21% and impurity A content of 0.37%.

[0049] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50 °C, add dropwise a 20% sodium carbonate solution to adjust the pH to 8, stir to dissolve, cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.40%, and the impurity A content is 0.08%.

[0050] The filtered material was dissolved in 50 ml of methanol at 25-30 °C, and a 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2-3. The solution was then cooled to 0-10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 8.07 g, the yield was 80.7%, the purity was 99.62%, and the impurity A content was 0.08% (purity diagram shown). Figure 5 (As shown).

[0051] Example 4 The preparation of crude HDQ raw material is described in Example 3.

[0052] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50 °C, add 20% potassium carbonate solution dropwise to adjust pH to 9, stir to dissolve, cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.75%, and the impurity A content is 0.07%.

[0053] The filtrate was dissolved in 50 mL of methanol at 25–30 °C, and a 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 8.0 g, the yield was 80%, the purity was 99.65%, and the impurity A content was 0.04%.

[0054] Example 5 The preparation of crude HDQ raw material is described in Example 3.

[0055] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50 °C, add 20% sodium hydroxide solution to adjust pH to 10, stir to dissolve, cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.47%, and the impurity A content is 0.05%.

[0056] The filtrate was dissolved in 50 mL of methanol at 25–30 °C, and a 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 7.2 g, the yield was 72%, the purity was 99.79%, and the impurity A content was 0.02%.

[0057] Example 6 The preparation of crude HDQ raw material is described in Example 3.

[0058] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50 °C, add dropwise 20% sodium hydroxide solution to adjust pH to 11, stir to dissolve, cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.42%, and the impurity A content is 0.06%.

[0059] The filtered material was dissolved in 50 mL of methanol at 25–30 °C, and a 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 6.9 g, the yield was 69%, the purity was 99.76%, and the impurity A content was 0.03%. Example 7 The preparation of crude HDQ raw material is described in Example 3.

[0060] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50℃, add dropwise 20% sodium hydroxide solution to adjust pH to 9, stir to dissolve, cool to 0-10℃ to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.72%, and the impurity A content is 0.06%.

[0061] The filtrate was dissolved in 50 mL of ethanol at 25–30 °C, and 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 8.7 g, the yield was 87%, the purity was 99.36%, and the impurity A content was 0.05%. Example 8 The preparation of crude HDQ raw material is described in Example 3.

[0062] Add 30 mL of water to 10 g of crude HDQ raw material, heat to 50℃, add dropwise 20% sodium hydroxide solution to adjust pH to 9, stir to dissolve, cool to 0-10℃ to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 98.84%, and the impurity A content is 0.07%.

[0063] The filtered material was dissolved in 50 mL of tetrahydrofuran at 25–30 °C, and 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was then cooled to 0–10 °C to induce crystallization. After filtration, the crystals were dried under vacuum at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 7.3 g, the yield was 73%, the purity was 99.86%, and the impurity A content was 0.03%. Comparative Example 1 The preparation of crude HDQ raw material is described in Example 3.

[0064] 10g of crude HDQ raw material was added to 30mL of 50% (v / v) ethanol aqueous solution, heated to 50℃, stirred to dissolve, then cooled to 0-10℃ to crystallize, filtered, yielding 8.6g of HDQ product, with a yield of 86%, HPLC purity of 98.67%, and impurity A content of 0.32% (purity diagram shown in figure). Figure 6 (As shown).

[0065] Comparative Example 2 Referring to the purification method disclosed in patent publication number CN112745262A, the specific operation is as follows:

[0066] Add 30g of compound 1a and 0.6mL of DMA to a 250mL reaction flask. Add 75g of aluminum trichloride in portions while stirring. Heat to 130-140℃ and react. After the reaction is complete as detected by TLC, slowly add 300mL of toluene to the reaction solution, then slowly pour into 300mL of ice water. Filter the precipitated solid and dry at 80℃ under normal pressure for 12h to obtain 15g of pink solid. The HPLC purity is 92.68%, and the impurity A content is 0.31% (purity diagram shown). Figure 7 (As shown).

[0067] Comparative Example 3 The preparation of crude HDQ raw material is described in Example 3.

[0068] Add 30 mL of water to the crude HDQ raw material, heat to 50 °C, stir to dissolve, then cool to 0-10 °C to precipitate crystals, filter, and obtain the filtrate. The purity of the filtrate is 97.94%, and the impurity A content is 0.28% (purity diagram shown). Figure 8 (As shown).

[0069] The foregoing examples are merely illustrative, used to explain some features of the method described in this invention. The appended claims are intended to claim the broadest possible scope, and the embodiments presented herein are demonstrated by the applicant's actual experimental results. Therefore, the applicant intends that the appended claims are not limited by the selection of examples illustrating the features of the invention. Some numerical ranges used in the claims also include sub-ranges within them, and variations within these ranges should also be interpreted as being covered by the appended claims where possible.

Claims

A method for purifying 1,3,4-dihydro-7-hydroxy-2(1H)-quinolinone, characterized in that, The crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone was dissolved, and the pH was adjusted to alkaline. Crystallization was then carried out to obtain purified 3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

2. The purification method according to claim 1, characterized in that, The alkaline pH is 7.5-13.

3. The purification method according to claim 1, characterized in that, The pH is adjusted by adding an alkaline solution; the alkaline solution is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

4. The purification method according to claim 1, characterized in that, The crystallization is a cooling crystallization.

5. The purification method according to claim 4, characterized in that, The cooling endpoint temperature for the cooling crystallization is 0-10℃.

6. The purification method according to claim 1, characterized in that, Dissolution is selected from at least one of the following (a) to (c): (a) The solvent used for dissolution is selected from one or more solvents, such as water and alcohols; (b) The crude product is heated to 30-70℃ to dissolve; (c) The mass-to-volume ratio of crude product to solvent is ≤1g:1mL.

7. The purification method according to claim 1, characterized in that, After crystallization, the following steps are also taken: the precipitate is filtered, then dissolved further, the pH is adjusted to acidic, crystallization is carried out, and the precipitate is filtered to obtain purified 3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

8. The purification method according to claim 7, characterized in that, Select from at least one of the following (d) to (f): (d) The solvent used to dissolve the precipitate is selected from one or more of alcohol solvents, ketone solvents, and ether solvents; (e) The acid used to adjust the pH is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid; (f) Adjust the pH to 2-5.

9. The purification method according to any one of claims 1-8, characterized in that, The crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone contains 0.10-1.0% impurity A; the structural formula of impurity A is shown below: 。 10. The purification method according to any one of claims 1-8, characterized in that, The method for preparing crude 3,4-dihydro-7-hydroxy-2(1H)-quinolinone is as follows: Using carboxylic acid esters and chlorobenzene as reaction solvents and aluminum trichloride as catalyst, compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 60-120℃ to generate 3,4-dihydro-7-hydroxy-2(1H)-quinolinone; the reaction formula for the preparation method is shown below: 。

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