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

Abstract

The invention discloses a preparation method of 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone and a preparation method of the 3, 4-dihydro-7-hydroxy-2 (1H)- According to the preparation method, carboxylic ester and chlorobenzene are used as reaction solvents, aluminum trichloride is used as a catalyst, and a compound 1a is subjected to an intramolecular Friedel-Crafts alkylation reaction at 60-120 DEG C to generate the 3, 4-dihydro-7-hydroxy-2 (1H)-quinolinone. According to the preparation method, the reaction temperature can be reduced, the safety risk can be reduced, the reaction conversion rate of the product can be improved, a reaction system is a flowing homogeneous phase instead of a molten state, quenching is facilitated, the requirement for production equipment is reduced, reaction conditions are milder, and the method is suitable for industrial large-scale production.

Description

Technical Field

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

[0002] Currently available medications for treating schizophrenia include aripiprazole and brexpiprazole. Aripiprazole, a quinolone derivative, is a third-generation atypical antipsychotic and the first dopamine system stabilizer. It is significantly effective for both positive and negative symptoms of schizophrenia and can be used to treat the condition, significantly improving these symptoms. It was approved by the FDA in November 2002 for the treatment of schizophrenia. Bripiprazole, also a third-generation atypical antipsychotic, has been proven effective not only in improving schizophrenia symptoms but also in preventing relapse.

[0003] Compound 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (HDQ) is an important intermediate in the synthesis of aripiprazole. Improving its quality and yield will be of great significance for improving the quality of aripiprazole raw material and reducing production costs.

[0004] Patent publication number CN112745262A discloses a method for preparing intermediate II (7-hydroxy-3,4-dihydro-1H-quinoline-2-one). The method uses a high-boiling-point solvent (specifically N,N-dimethylacetamide) as the reaction solvent and holds the reaction at 130-140℃. Intermediate II is prepared by intramolecular Friedel-Crafts alkylation reaction. This reaction avoids the problem of catalyst sublimation during the melting reaction by using a high-boiling-point solvent method. The yield of intermediate II is about 60%.

[0005] However, the above method has the following problems: (1) The reaction needs to be carried out at a high temperature, which consumes a lot of energy and the product conversion rate is still low; (2) The reaction must be carried out at a high temperature and with a small amount of solvent. The reaction will not proceed at low temperatures such as below 120°C, and the use of a large amount of solvent will slow down the reaction rate or even prevent the reaction from proceeding. Since the temperature of the reaction liquid is high, in order to avoid the danger of adding solvent at high temperature, the reaction system needs to be cooled down before the solvent can be added for post-processing. However, since a small amount of solvent is used in the reaction system, the product will precipitate and solidify in large quantities in the form of solid after cooling. It cannot be stirred and needs to be heated again to dissolve the solid before post-processing. This makes the post-processing process cumbersome and unsuitable for large-scale production. Summary of the Invention

[0006] To address the aforementioned problems in the existing technology, the primary objective of this invention is to provide a method for preparing 3,4-dihydro-7-hydroxy-2(1H)-quinolinone. This method uses carboxylic acid esters and chlorobenzene as reaction solvents, enabling the reaction system to disperse and dissolve, which is beneficial for production operations. It avoids the difficulties associated with using solvent-free systems or systems requiring only small amounts of solvent, making it suitable for industrial scale-up production. Furthermore, it lowers the reaction temperature and reduces safety risks. The reaction system of this method can significantly improve the reaction conversion rate and yield of the product.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention claims protection for a method for preparing 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, using a carboxylic acid ester and chlorobenzene as reaction solvents, and aluminum trichloride as a catalyst. Compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 60-120°C to generate 3,4-dihydro-7-hydroxy-2(1H)-quinolinone; the reaction formula for the preparation method is shown below: .

[0008] The inventors discovered that, using carboxylic acid esters and chlorobenzene as reaction solvents, 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (HDQ) can be prepared from compound 1a via a conventional intramolecular Friedel-Crafts alkylation reaction at a relatively low temperature. Furthermore, using carboxylic acid esters and chlorobenzene as reaction solvents allows for dispersion of the reaction system, facilitating stirring during production; and after the reaction, the product dissolves in the reaction solvent, ensuring smooth stirring and facilitating material transfer, quenching, and other operations, thus improving production convenience.

[0009] The method described in this invention solves the problems of existing reactions requiring high temperatures, resulting in high energy consumption and low product conversion and yield. It also addresses the difficulties in production caused by using solvent-free systems or only adding a small amount of solvent in intramolecular Friedel-Crafts alkylation reactions, leading to cumbersome post-processing and unsuitability for scale-up production.

[0010] Preferably, the carboxylic acid ester is a carboxylic acid ester containing 2-6 carbon atoms; preferably, the carboxylic acid ester is selected from at least one of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and tert-butyl acetate. More preferably, the carboxylic acid ester is selected from at least one of ethyl acetate, n-propyl acetate, and isopropyl acetate. More preferably, the carboxylic acid ester is selected from ethyl acetate. Under these preferred conditions, the preparation method has a higher reaction conversion rate, and the product obtained has a higher HDQ content.

[0011] Preferably, ethyl acetate and chlorobenzene are used as reaction solvents, or isopropyl acetate and chlorobenzene are used as reaction solvents.

[0012] Preferably, the volume ratio of carboxylic acid ester to chlorobenzene is 1:0.1-20; more preferably, the volume ratio is 1:1-12; more preferably, the volume ratio is 1:3-7; even more preferably, the volume ratio is 1:5-7. Under these preferred conditions, the preparation method has a higher reaction conversion rate, and the obtained product has a higher HDQ content. More specifically, the volume ratio of carboxylic acid ester to chlorobenzene can be 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, etc., or any range formed by the above values, such as 1:1-14, 1:3-10, etc., and the present invention is not limited thereto.

[0013] Preferably, compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 70-100°C. More preferably, compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 80-90°C. Under these preferred conditions, the preparation method has a higher reaction conversion rate, and the obtained product has a higher content of HDQ. More specifically, the reaction temperature of the intramolecular Friedel-Crafts alkylation reaction can be 73°C, 75°C, 78°C, 80°C, 83°C, 85°C, 88°C, 90°C, 95°C, 98°C, etc., or any range formed by the above values, such as 73-90°C, 83-93°C, etc., and the present invention is not limited thereto.

[0014] 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 1:3-10; even more preferably, the molar ratio of the catalyst to compound 1a is 1:3-7. Under these preferred conditions, the preparation method has a higher reaction conversion rate, and the obtained product has a higher content of HDQ. More specifically, the molar ratio of the catalyst to compound 1a can be 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, etc., or any range formed by the above values, and the present invention is not limited thereto.

[0015] 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 2-15 mL / g; even more preferably, the volume-to-mass ratio of the reaction solvent to compound 1a is 4-10 mL / g. Under these preferred conditions, the preparation method has a higher reaction conversion rate, and the obtained product has a higher content of HDQ. More specifically, the volume-to-mass ratio of the reaction solvent to compound 1a can be 3 mL / g, 5 mL / g, 7 mL / g, 9 mL / g, 11 mL / g, 13 mL / g, 15 mL / g, 17 mL / g, 19 mL / g, etc., or any range formed by the above values, and the present invention is not limited thereto.

[0016] Preferably, the reaction time of the intramolecular Friedel-Crafts alkylation reaction is ≥6 h; more preferably, the reaction time is 6-36 h; even more preferably, the reaction time is 12-20 h. Under these preferred conditions, the preparation method has a higher reaction conversion rate, and the obtained product has a higher HDQ content.

[0017] Preferably, the catalyst is added to the reaction system at ≤25°C.

[0018] Preferably, the preparation method further includes a post-processing step, which is to dissolve the crude product generated by the reaction, then adjust the pH to alkaline, crystallize and precipitate, and obtain purified 3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

[0019] As shown below, during the preparation of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, impurity A is generated, with a relative retention time (RRT) of 0.87 in the HPLC chromatogram. The above post-processing steps can significantly improve the purity of the final product, reducing the content of impurity A to less than 0.10%, thus meeting pharmaceutical requirements.

[0020] Specifically, the structural formulas of HDQ and impurity A are shown below: .

[0021] Preferably, the alkaline pH is 7.5-13.

[0022] Preferably, the pH is adjusted by adding an alkaline solution.

[0023] Preferably, the crystallization is carried out by cooling crystallization.

[0024] Preferably, the cooling endpoint temperature of the cooling crystallization is 0-10℃.

[0025] Preferably, the conditions for dissolving the crude product generated in the reaction are 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.

[0026] 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.

[0027] 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.

[0028] Preferably, the solvent used to dissolve the precipitate is selected from one or more of alcohol solvents, ketone solvents, and ether solvents.

[0029] Compared with the prior art, the present invention has the following beneficial effects: (1) In this invention, 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (HDQ) can be prepared from compound 1a via an intramolecular Friedel-Crafts alkylation reaction at a relatively low temperature using carboxylic acid esters and chlorobenzene as reaction solvents. The preparation method allows the reaction system to be dispersed, which is beneficial for stirring during the production process; and after the reaction is completed, the product can be dissolved in the reaction solvent, which allows for smooth stirring and facilitates material transfer, quenching, and other operations, thereby improving the convenience of production.

[0030] (2) The preparation method provided by the present invention solves the problem that the existing reaction needs to be carried out at a high temperature, resulting in high energy consumption and low product conversion rate and yield. It also solves the problem that the existing intramolecular Friedel-Crafts alkylation reaction uses a solvent-free system or can only add a small amount of solvent system, which leads to complicated post-processing and is not suitable for large-scale production.

[0031] (3) By exploring and screening reaction conditions, this invention greatly improves the reaction conversion rate of product HDQ and increases the yield of reaction products. Attached Figure Description

[0032] Figure 1 and Figure 2 The images shown are the proton and carbon spectra of the HDQ prepared in Example 1.

[0033] Figure 3 This is a schematic diagram showing the purity of HDQ prepared in Example 1.

[0034] Figure 4 This is a schematic diagram showing the purity of HDQ prepared in Example 2.

[0035] Figure 5 This is a schematic diagram showing the purity of HDQ prepared in Example 3.

[0036] Figure 6 This is a schematic diagram showing the purity of HDQ prepared in Comparative Example 1.

[0037] Figure 7 This is a schematic diagram illustrating the purity of HDQ prepared in Comparative Example 2. Detailed Implementation

[0038] 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.

[0039] Example 1 (1) Add 10.00g of compound 1a and 60mL of ethyl acetate / chlorobenzene solution (V / V=1:6) to a 250mL reaction flask. Add 28.05g of aluminum trichloride while maintaining the temperature below 25℃. Heat to 80℃ and react for 20h. Monitor the complete conversion of the starting material by TLC. Cool to 20~30℃, add dropwise pre-cooled to 0~10℃, quench in 100mL of 1% hydrochloric acid water, remove the organic solvent by rotary evaporation, precipitate the solid, cool to 20~25℃, filter, and obtain crude HDQ with a purity of 85.3% and impurity A content of 0.41%. The proton and carbon spectra of HDQ are as follows: Figure 1 and Figure 2 As shown. The reaction formula for the preparation method in step (1) above is as follows: .

[0040] (2) Add 30 mL of water to 10 g of crude HDQ, heat to 50 °C, add 20% sodium hydroxide solution to adjust pH to 9, stir to dissolve, cool to 0-10 °C to crystallize, filter to obtain wet filter product. The purity of wet filter product is 98.77%, and the content of impurity A is 0.09%.

[0041] 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 wet product was vacuum dried 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).

[0042] Example 2 (1) Add 10.00g of compound 1a and 60mL of ethyl acetate / chlorobenzene (V / V=1:6) to a 250mL reaction flask. Add 28.05g of aluminum trichloride while maintaining the temperature below 25℃. Refrigerate at 80℃ for 20h. Monitor the complete conversion of the starting material by TLC. Cool down to 20~30℃, add dropwise pre-cooled to 0~10℃, quench in 100mL of 1% hydrochloric acid water, remove the organic solvent by rotary evaporation, precipitate the solid, cool down to 20~25℃, filter, and obtain crude HDQ product.

[0043] (2) Add 35 mL of water to 10 g of crude HDQ, heat to 55 °C, add 20% potassium hydroxide solution to adjust pH to 9, stir to dissolve, cool to 0-10 °C to crystallize, filter to obtain wet filter product. The purity of wet filter product is 97.6%, and the content of impurity A is 0.07%.

[0044] The wet filtered product was dissolved in 50 mL of methanol at 25–30 °C. A 1 M hydrochloric acid solution was added dropwise to adjust the pH to 2–3. The solution was cooled to 0–10 °C to induce crystallization. After filtration, the wet product was vacuum dried at 60 °C to obtain a white solid, HDQ. The weight of the white solid HDQ was 8.4 g, with a yield of 84.4%, a purity of 99.54%, and an impurity A content of 0.04% (purity diagram shown). Figure 4 (As shown).

[0045] Example 3 (1) Add 1.0 kg of compound 1a and 6 L of ethyl acetate / chlorobenzene solution (V / V=1:6) to a 250 mL reaction flask, and add 2.8 kg of aluminum trichloride (4 eq) while maintaining the temperature below 25 °C. Heat to 80 °C and react for 20 h. Monitor the complete conversion of the raw materials by TLC. Cool to 20~30 °C, add dropwise pre-cooled to 0~10 °C, quench in 10 L of 1% hydrochloric acid water, remove organic solvent by rotary evaporation, precipitate solid, cool to 20~25 °C, filter, and obtain 820 g of crude HDQ product with a purity of 86.21% and impurity A content of 0.37%.

[0046] (2) Add 30 mL of water to 10 g of crude HDQ, heat to 50 °C, add 20% sodium hydroxide solution to adjust pH to 8, stir to dissolve, cool to 0-10 °C to crystallize, filter to obtain wet filter product. The purity of wet filter product is 98.40%, and the content of impurity A is 0.08%.

[0047] The wet filtered product was dissolved in 50 ml of methanol at 25-30°C. A 1M hydrochloric acid solution was added dropwise to adjust the pH to 2-3. The solution was cooled to 0-10°C to induce crystallization. After filtration, the wet product was vacuum dried 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).

[0048] Example 4 investigates the effect of different solvents on the reaction process. Following the operating steps of Example 1, 10.00 g of compound 1a and 100 mL of reaction solvent were added to a 250 mL reaction flask. 28.05 g of aluminum trichloride was added while maintaining the temperature below 25 °C. The temperature was raised to 80 °C and reacted for 20 h. Samples were taken, and the HPLC detection results are shown in Table 1 below.

[0049] Table 1

[0050] As shown in Table 1 above, the reaction results are better when ethyl acetate / chlorobenzene and isopropyl acetate / chlorobenzene are used as solvents, especially ethyl acetate / chlorobenzene.

[0051] Example 5 investigates the effect of different solvent amounts on the reaction process. Following the operating steps of Example 1, 10.00 g of compound 1a and different volumes of ethyl acetate / chlorobenzene (volume ratio 1:4) were added to the reaction flask. 28.05 g of aluminum trichloride was added while maintaining the temperature below 25°C. The temperature was raised to 80°C and reacted for 20 h. Samples were taken, and the HPLC detection results are shown in Table 2 below.

[0052] Table 2

[0053] Example 6 investigated the ratio of ethyl acetate / chlorobenzene mixed solvent Following the operating steps of Example 1, 10.00 g of compound 1a and ethyl acetate / chlorobenzene in different volume ratios (total amount 10 mL / g) were added to the reaction flask. 28.05 g of aluminum trichloride was added while maintaining the temperature below 25°C. The temperature was raised to 80°C and reacted for 20 h. Samples were taken, and the HPLC detection results are shown in Figure 3 below.

[0054] Table 3

[0055] Example 7 investigated the reaction temperature Following the operating steps of Example 1, 10.00 g of compound 1a and 60 mL of ethyl acetate / chlorobenzene mixed solvent (volume ratio 1:4) were added to the reaction flask. 28.05 g of aluminum trichloride was added while maintaining the temperature below 25°C. The mixture was heated to different temperatures and reacted for 20 h. Samples were taken, and the HPLC detection results are shown in Table 4 below.

[0056] Table 4

[0057] Example 8 investigates the effect of the type of catalyst on the reaction. Following the operating steps of Example 1, 10.00 g of compound 1a and 60 mL of ethyl acetate / chlorobenzene mixed solution (volume ratio 1:4) were added to the reaction flask. Different catalysts (all 4 eq) were added while maintaining the temperature below 25°C. The temperature was raised to 80°C and reacted for 20 h. Samples were taken, and the HPLC detection results are shown in Table 5 below.

[0058] Table 5

[0059] Example 9 investigates the effect of aluminum trichloride dosage on the reaction. Following the operating steps of Example 1, 10.00 g of compound 1a and 60 mL of ethyl acetate / chlorobenzene (volume ratio 1:4) were added to the reaction flask. The temperature was controlled below 25°C, and different amounts of aluminum trichloride catalyst were added. The temperature was raised to 80°C and reacted for 20 h. Samples were taken, and the HPLC detection results are shown in Table 6 below.

[0060] Table 6

[0061] Example 10 examines the effect of reaction time on the reaction. Following the operating steps of Example 1, 10.00 g of compound 1a and 60 mL of ethyl acetate / chlorobenzene (volume ratio 1:4) were added to the reaction flask. The temperature was controlled below 25°C, and 4 eq of aluminum trichloride catalyst were added. The temperature was raised to 80°C and the reaction was carried out for different times. The HPLC results of the samples are shown in Table 7 below.

[0062] Table 7

[0063] Comparative Example 1 (1) Add 10.00g of compound 1a, 5g of N,N-dimethylacetamide (DMAC), and 33.39g of aluminum trichloride to a 250 mL reaction flask. Heat to 130~140℃ and react for 5h. Monitor the conversion of the raw materials by TLC until complete. Cool down to 20~30℃. The reaction system solidifies and becomes difficult to stir.

[0064] Toluene was added, and the mixture was heated to 100°C to dissolve the solid. The solid was then quenched dropwise in hydrochloric acid solution to obtain a pale pink solid, HDQ. The weight of the pale pink solid HDQ was 4.3 g, with a yield of 52.6% and a purity of 83.25%.

[0065] (2) The light pink solid HDQ was recrystallized from ethanol and water to obtain 3.7g of HDQ with a purity of 96.34% (see purity diagram). Figure 6 As shown in the figure, the content of impurity A was 0.49%, and the yield was 45.2%.

[0066] Comparative Example 2 (1) Add 10.00g of compound 1a and 33.39g of aluminum trichloride to a 250 mL reaction flask, heat to 130~140℃ and react for 6h. Monitor the conversion of the raw materials by TLC until complete. Cool down to 80-90℃, the reaction system solidifies and is difficult to stir.

[0067] Toluene was added, and the mixture was heated to 100°C to dissolve the solid. The solid was then quenched dropwise in hydrochloric acid solution to obtain a pale pink solid, HDQ. After drying, the solid weighed 4.1 g, yielding 49% and a purity of 79.31%.

[0068] (2) The light pink solid HDQ was recrystallized from ethanol and water to obtain 3.6 g of HDQ with a purity of 97.0% (see purity diagram). Figure 7 As shown in the figure, the content of impurity A is 0.57%, and the yield is 40%.

[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 preparing 1,3,4-dihydro-7-hydroxy-2(1H)-quinolinone, characterized in that, 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: 。 2. The preparation method according to claim 1, characterized in that, The carboxylic acid ester is a carboxylic acid ester containing 2-6 carbon atoms; Preferably, the carboxylic acid ester is selected from at least one of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and tert-butyl acetate.

3. The preparation method according to claim 2, characterized in that, Ethyl acetate and chlorobenzene can be used as reaction solvents, or isopropyl acetate and chlorobenzene can be used as reaction solvents.

4. The preparation method according to claim 1 or 3, characterized in that, The volume ratio of carboxylic acid ester to chlorobenzene is 1:0.1-20; Preferably, the volume ratio of carboxylic acid ester to chlorobenzene is 1:1-12; Preferably, the volume ratio of carboxylic acid ester to chlorobenzene is 1:3-7.

5. The preparation method according to claim 1, characterized in that, Compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 70-100 °C; Preferably, compound 1a undergoes an intramolecular Friedel-Crafts alkylation reaction at 80-90°C.

6. The preparation method according to claim 1, characterized in that, The molar ratio of the catalyst to compound 1a is 1:2.5-12; Preferably, the molar ratio of the catalyst to compound 1a is 1:3-10; Preferably, the molar ratio of the catalyst to compound 1a is 1:3-7.

7. The preparation method according to claim 1, characterized in that, The volume-to-mass ratio of the reaction solvent to compound 1a is 1-20 mL / g; Preferably, the volume-to-mass ratio of the reaction solvent to compound 1a is 2-15 mL / g; Preferably, the volume-to-mass ratio of the reaction solvent to compound 1a is 4-10 mL / g.

8. The preparation method according to claim 1, characterized in that, The reaction time for intramolecular Friedel-Crafts alkylation is ≥6 h; Preferably, the reaction time for the intramolecular Friedel-Crafts alkylation reaction is 6-36 h; Preferably, the reaction time for the intramolecular Friedel-Crafts alkylation reaction is 12-20 h.

9. The preparation method according to claim 1, characterized in that, Add the catalyst to the reaction system at ≤25℃.

10. The preparation method according to claim 1, characterized in that, The preparation method further includes a post-processing step; the post-processing step is: dissolving the crude product generated by the reaction, then adjusting the pH to alkaline, crystallizing out, and obtaining purified 3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

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