Clean production method of 1, 4-dihydroxy quinone medical intermediate for antitumor drugs

Abstract

The invention discloses a clean production method of a 1, 4-dihydroxy anthraquinone medical intermediate for an anti-tumor drug, a 1, 4-dihydroxy anthraquinone product is produced by the steps of feeding, reaction, hydrolysis, suction filtration and drying, and mother liquor wastewater generated in the suction filtration step is sequentially subjected to cooling crystallization and resin adsorption, so that the 1, 4-dihydroxy anthraquinone medical intermediate is obtained. Phthalic acid is obtained after phthalic acid desorption, resin regeneration and phthalic acid refining treatment, phthalic acid is dried and then reused for synthesis of the 1, 4-dihydroxy anthraquinone medical intermediate, and filtrate is merged into the next batch of synthesis mother liquor wastewater to be treated. The resource recycling of the mother liquor wastewater and the clean production of the 1, 4-dihydroxyquinone can be realized, and the resource is effectively saved.

Description

Technical Field

[0001] The present invention relates to the technical field of the production and application of 1,4-dihydroxyanthraquinone, and particularly relates to a clean production method of a 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs. Background Art

[0002] In recent years, the medicinal value of 1,4-dihydroxyanthraquinone in anti-cancer and anti-tumor aspects has attracted much attention. It can be used as an intermediate to synthesize other organic compounds with biological activities and pharmacological effects. Research shows that 1,4-dihydroxyanthraquinone not only has an obvious inhibitory effect on the Casein Kinase2 tumor closely related to HIV-1, but can also be used as a photosensitizer that has a damaging effect on DNA. Moreover, the coordination polymer formed by equimolar 1,4-dihydroxyanthraquinone and Y3+ can nearly double its efficiency of photo-damaging DNA. Based on this, 1,4-dihydroxyanthraquinone can be developed as a drug for clinical treatment, and 1,4-dihydroxyanthraquinone can also be used as an intermediate for synthesizing anti-tumor drugs. Currently, compounds with HPV cytotoxicity and a series of compounds that can overcome the drug resistance of cancer cells to doxorubicin have been synthesized using 1,4-dihydroxyanthraquinone as a raw material. Mitoxantrone analogs with toxicity and inhibitory effects on J774A.1 macrophages have been synthesized using 1,4-dihydroxyanthraquinone as a raw material.

[0003] As a pharmaceutical intermediate, the anti-tumor activity of 1,4-dihydroxyanthraquinone is equivalent to or slightly higher than that of doxorubicin, and significantly higher than that of cyclophosphamide, fluorouracil, methotrexate, vincristine, and cytarabine. Moreover, it has a wide anti-tumor spectrum. It can not only be used to synthesize dyes and compounds with anti-tumor activities, but can also be used as a potential material for preparing sensors and LED devices. The two active para a-hydroxyl groups at the 1,4 positions make 1,4-dihydroxyanthraquinone relatively easy to undergo substitution reactions to obtain its derivatives, and it has broad application prospects in industrial production.

[0004] However, in the traditional production process of 1,4-dihydroxyanthraquinone, the mother liquor wastewater generated is directly treated as waste, and it is impossible to achieve resource recycling and clean production of 1,4-dihydroxyanthraquinone, resulting in serious waste of resources. Summary of the Invention

[0005] The purpose of the present application is to provide a clean production method of a 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs, so as to solve the problems that in the traditional production process of 1,4-dihydroxyanthraquinone, it is impossible to achieve resource recycling and clean production of 1,4-dihydroxyanthraquinone, and there is serious waste of resources.

[0006] To solve the above technical problems, the present application provides a clean production method of a 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs, including:

[0007] Charging: 9.20 g of 96% sulfuric acid was introduced into the reaction kettle and stirred at 120 r / min. 1.0 g of boric acid and 3.88 g of phthalic anhydride were slowly added in sequence. The reaction kettle was gradually heated to 120 °C by a high-low temperature integrated machine. After the materials were completely dissolved, 1.60 g of p-chlorophenol was added dropwise;

[0008] Reaction: After the charging was completed, the reaction kettle was gradually heated to 50 °C by the high-low temperature integrated machine and kept at this temperature for 1 h. The high-low temperature integrated machine was adjusted for the second time to gradually heat the reaction kettle to 180 °C and keep at this temperature for 2 h. The high-low temperature integrated machine was adjusted for the third time to gradually heat the reaction kettle to 200 °C and keep at this temperature for 8 - 10 h to obtain a condensation liquid;

[0009] Hydrolysis: 36.5 g of water was added to the hydrolysis tank and stirred. The condensation liquid was slowly added dropwise to the water. After continuously stirring and keeping at a temperature of 95 - 105 °C for 4 h, crude 1,4-dihydroxyanthraquinone crystals precipitated out in hot water;

[0010] Filtration by suction: The hydrolysis liquid at 95 - 105 °C was added to the vacuum filtration device in batches. The crude 1,4-dihydroxyanthraquinone crystals and the mother liquor wastewater were collected. The crude 1,4-dihydroxyanthraquinone crystals were washed with hot water at 85 °C and then filtered by suction again to obtain 1,4-dihydroxyanthraquinone crystals;

[0011] Drying: The 1,4-dihydroxyanthraquinone crystals were added to the drying kettle and dried under negative pressure at a temperature of 120 - 130 °C and a pressure of -0.07 Mpa. After drying, the temperature was lowered to below 50 °C to obtain the 1,4-dihydroxyanthraquinone product;

[0012] Cooling crystallization: The mother liquor wastewater was cooled and then subjected to cooling crystallization. The filtrate Ⅰ and the filter cake Ⅰ were obtained by filtration. The filter cake Ⅰ was crude phthalic acid;

[0013] Resin adsorption: The collected filtrate Ⅰ was injected from the upper end of the adsorption column filled with 100 ml of different types of styrene-based macroporous resins for adsorption, and different resin volume multiples were adsorbed. The adsorption liquid was collected;

[0014] Desorption of phthalic acid and resin regeneration: The resin after adsorption saturation was dried. Different adsorption liquids were injected from the bottom end of the adsorption column for reverse elution desorption. After desorption, it was dried and the alkaline desorption liquid was collected;

[0015] Purification of phthalic acid: Using the alkali desorption liquid as the bottom water, adding filter cake I, heating up, adjusting the pH to 8 - 9 with 30% sodium hydroxide solution and then filtering. The filtrate is collected and the pH is adjusted to 2 - 7 with the adsorption liquid. After cooling to below 15°C, filtering to obtain filtrate II and filter cake II. The filter cake II is phthalic acid. After drying the filter cake II, it is recycled. The filtrate II is incorporated into the next batch of synthetic mother liquor wastewater for treatment.

[0016] As a preferred embodiment, in a method for the clean production of a 1,4 - dihydroxyanthraquinone pharmaceutical intermediate for anti - tumor drugs, after collecting the alkali desorption liquid in the phthalic acid desorption and resin regeneration steps, it further includes: Injecting hot water from the bottom end of the adsorption column for backwashing. After the backwashing is completed, the collected backwash liquid is sent to the resin adsorption step for adsorption treatment again.

[0017] As a preferred embodiment, in a method for the clean production of a 1,4 - dihydroxyanthraquinone pharmaceutical intermediate for anti - tumor drugs, the HCl gas generated in the reaction step is introduced into a water - washing tank, and 2.5 g of water is used to absorb and dissolve it to form dilute hydrochloric acid.

[0018] As a preferred embodiment, in a method for the clean production of a 1,4 - dihydroxyanthraquinone pharmaceutical intermediate for anti - tumor drugs, in the feeding step, the increase amount of single - time temperature rise using the high - low temperature integrated machine ≤ 30°C.

[0019] It should be detailed in the scheme that in a method for the clean production of a 1,4 - dihydroxyanthraquinone pharmaceutical intermediate for anti - tumor drugs, after collecting the adsorption liquid in the resin adsorption step, it further includes detecting the COD content and sulfuric acid acidity of the adsorption liquid and collecting the detection data.

[0020] As a preferred embodiment, in a method for the clean production of a 1,4 - dihydroxyanthraquinone pharmaceutical intermediate for anti - tumor drugs, the washing water obtained in the suction filtration step is recycled to the hydrolysis step.

[0021] Compared with the prior art, the method for the clean production of a 1,4 - dihydroxyanthraquinone pharmaceutical intermediate for anti - tumor drugs provided by the present invention uses feeding, reaction, hydrolysis, suction filtration, and drying steps to produce 1,4 - dihydroxyanthraquinone products. And the mother liquor wastewater generated in the suction filtration step is successively subjected to cooling crystallization, resin adsorption, phthalic acid desorption, resin regeneration, and phthalic acid purification treatment to obtain phthalic acid. After drying the phthalic acid, it is recycled for the synthesis of 1,4 - dihydroxyanthraquinone pharmaceutical intermediates, and the filtrate is incorporated into the next batch of synthetic mother liquor wastewater for treatment. It can realize the resource - based recycling of mother liquor wastewater and the clean production of 1,4 - dihydroxyanthraquinone, effectively saving resources. Description of the Drawings

[0022] To more clearly illustrate the technical solution of the present application, the following will briefly introduce the attached drawings required in the embodiments. Obviously, for those of ordinary skill in the art, without creative efforts, other attached drawings can also be obtained based on these drawings.

[0023] Figure 1 Schematic diagram of the process for the clean production of the 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs provided by the embodiment of the present application;

[0024] Figure 2 Main reaction equation provided by the embodiment of the present application;

[0025] Figure 3 Hydrolysis reaction equation provided by the embodiment of the present application;

[0026] Figure 4 Trend diagram of the effect of reaction temperature on the yield of 1,4-dihydroxyanthraquinone provided by the embodiment of the present application;

[0027] Figure 5 Trend diagram of the degree of side reactions at different reaction temperatures provided by the embodiment of the present application;

[0028] Figure 6 Trend diagram of the effect of boric acid feeding amount on the yield of 1,4-dihydroxyanthraquinone provided by the embodiment of the present application;

[0029] Figure 7 Schematic diagram of the degree of side reactions occurring at different sulfuric acid concentrations provided by the embodiment of the present application;

[0030] Figure 8 Trend diagram of the yield of 1,4-dihydroxyanthraquinone at different sulfuric acid concentrations provided by the embodiment of the present application. Detailed implementation manners

[0031] In order to enable those skilled in the art to better understand the technical solution in the present application, the following will clearly and completely describe the technical solution in the embodiment of the present application in conjunction with the attached drawings.

[0032] The core of the present application is to provide a clean production method for the 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs, which solves the problems that in the traditional production process of 1,4-dihydroxyanthraquinone, resource recycling and clean production of 1,4-dihydroxyanthraquinone cannot be achieved, and serious resource waste occurs.

[0033] Figure 1 Schematic diagram of the process for the clean production of the 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs provided by the embodiment of the present application, Figure 2 Main reaction equation provided by the embodiment of the present application,Figure 3 A hydrolysis reaction equation provided by an embodiment of the present application Figure 4 A trend chart of the influence of reaction temperature on the yield of 1,4-dihydroxyanthraquinone provided by an embodiment of the present application Figure 5 A trend chart of the degree of side reactions at different reaction temperatures provided by an embodiment of the present application Figure 6 A trend chart of the influence of the boric acid feeding amount on the yield of 1,4-dihydroxyanthraquinone provided by an embodiment of the present application Figure 7 A schematic diagram of the degree of side reactions occurring under different sulfuric acid concentrations provided by an embodiment of the present application Figure 8 A trend chart of the yield of 1,4-dihydroxyanthraquinone under different sulfuric acid concentrations provided by an embodiment of the present application, see Figures 1 to 8 as shown

[0034] Example 1

[0035] A clean production method for a 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs, comprising:

[0036] Feeding: Inject 9.20 g of 96% sulfuric acid into the reaction kettle and stir at 120 r / min. Slowly add 1.00 g of boric acid and 3.88 g of phthalic anhydride in sequence. Gradually heat the reaction kettle to 120 °C using a high and low temperature integrated machine. After the materials are completely dissolved, start to dropwise add 1.60 g of p-chlorophenol. The reaction kettle in this step is a 10 L glass reaction kettle.

[0037] Reaction: After the feeding is completed, gradually heat the reaction kettle to 50 °C using a high and low temperature integrated machine, and keep the temperature for 1 h; adjust the high and low temperature integrated machine for the second time, gradually heat the reaction kettle to 180 °C, and keep the temperature for 2 h; adjust the high and low temperature integrated machine for the third time, gradually heat the reaction kettle to 200 °C, and keep the temperature for 8 - 10 h to obtain a condensation liquid;

[0038] Hydrolysis: Add 36.5 g of water to the hydrolysis tank and stir. Slowly flow the condensation liquid into the water, and keep stirring and heat preservation reaction at 95 - 105 °C for 4 h, then the crude product of 1,4-dihydroxyanthraquinone crystals can precipitate out in hot water;

[0039] Filtration: Add the hydrolysis liquid at 95 - 105 °C to the vacuum filtration device in batches, collect the crude product of 1,4-dihydroxyanthraquinone crystals and the mother liquor wastewater, wash the crude product of 1,4-dihydroxyanthraquinone crystals with 85 °C hot water and then conduct filtration again to obtain 1,4-dihydroxyanthraquinone crystals;

[0040] Drying: Add 1,4-dihydroxyanthraquinone crystals into a drying kettle, and conduct negative pressure drying at a temperature of 120 - 130°C and a pressure of -0.07 Mpa. After drying, cool down to below 50°C to obtain the 1,4-dihydroxyanthraquinone product. The drying kettle used in this step is a 30L stainless steel drying kettle, and start the reciprocating vacuum pump for the experiment to adjust the required pressure. After obtaining the 1,4-dihydroxyanthraquinone product, mix it thoroughly and take samples to send to the laboratory for testing.

[0041] Cooling crystallization: Cool down the mother liquor wastewater and then conduct cooling crystallization, filter to obtain filtrate I and filter cake I, and filter cake I is the crude phthalic acid.

[0042] Resin adsorption: Inject the collected filtrate I from the upper end of the adsorption column filled with 100m1 of different types of styrene-based macroporous resins for adsorption, and adsorb different resin volume multiples, and collect the adsorption liquid.

[0043] Desorption of phthalic acid and resin regeneration: Blow dry the resin after adsorption saturation, and inject different adsorption liquids from the bottom end of the adsorption column for reverse elution desorption; after desorption, blow dry and collect the alkali desorption liquid.

[0044] Purification of phthalic acid: Use the alkali desorption liquid as the bottom water, add filter cake I, heat up, adjust the pH = 8 - 9 with 30% sodium hydroxide solution and then filter, adjust the pH of the collected filtrate to 2 - 7 with the adsorption liquid, cool down to below 15°C, filter to obtain filtrate II and filter cake II, and filter cake II is phthalic acid. Dry filter cake II and recycle it, and incorporate filtrate II into the next batch of synthetic mother liquor wastewater for treatment. In this example, when recycling filter cake II, it needs to be reprocessed and then participate in the synthesis of the 1,4-dihydroxyanthraquinone pharmaceutical intermediate again.

[0045] Example 2

[0046] Based on Example 1, a clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs. In the step of phthalic acid desorption and resin regeneration, after collecting the alkali desorption liquid, it further includes: Inject hot water from the bottom end of the adsorption column for backwashing, and after washing, send the collected backwash liquid to the resin adsorption step for re-adsorption treatment.

[0047] Based on Example 1, a clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs. Pass the HCL gas generated in the reaction step into a water washing tank, and use 2.5g of water to absorb and dissolve it to generate dilute hydrochloric acid.

[0048] Based on Example 1, a clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs. In the feeding step, the increase amount of single-time temperature rise using a high and low temperature integrated machine ≤ 30°C.

[0049] On the basis of Example 1, a clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs. After collecting the adsorption liquid in the resin adsorption step, it further includes detecting the COD content and sulfuric acid acidity of the adsorption liquid and collecting the detection data.

[0050] On the basis of Example 1, a clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs. The washing water obtained in the filtration step is recycled to the hydrolysis step.

[0051] During the experiment, the experimental equipment used included 1 glass reaction kettle, 1 30L stainless steel drying kettle; 1 FLR series high and low temperature all-in-one machine; 1 electronic platform scale; 1 experimental reciprocating vacuum pump; 1 water ring vacuum pump; 1 1000ml measuring cylinder; 1 1000ml 5L suction filter flask; suction filter funnel; beakers and other utensils; other experimental equipment. The quality indexes of 1,4-dihydroxyanthraquinone produced by this production method are shown in Table 1.

[0052] Table 1 Quality Index Table of 1,4-Dihydroxyanthraquinone

[0053]

[0054] Effect of temperature on the yield of 1,4-dihydroxyanthraquinone:

[0055] Under the standard feeding amount, the yield of 1,4-dihydroxyanthraquinone and the degree of side reactions at different temperatures were investigated. The specific experimental data are shown in Table 2:

[0056] Table 2 Effect of Different Reaction Temperatures on the Yield of 1,4-Dihydroxyanthraquinone

[0057] Serial number Reaction temperature T / °C Yield W NO.1 180.00 0.56 NO.2 190.00 0.62 NO.3 200.00 0.90 NO.4 210.00 0.73 NO.5 220.00 0.65

[0058] From Table 2, a trend graph as shown in Figure 4 was obtained by plotting with origin; from Table 2 and Figure 4 it can be seen that during the process of the temperature rising from 180°C to 200°C, the yield of 1,4-dihydroxyanthraquinone gradually increases, while during the process of the temperature rising from 200°C to 220°C, the yield gradually decreases. If the temperature is too low, the reaction is incomplete and the reaction time is too long; if the temperature is too high, the side reactions increase and the yield will decrease significantly. Considering comprehensively, the range of 200°C is selected as the optimal reaction temperature.

[0059] Figure 5 Show the side reaction situation during the chloro-hydroxyl reaction at different temperatures. From Figure 5It can be seen that when T = 180-190 ° C, the reaction is relatively slow, the yield is high, but the reaction time is slightly extended; when T = 190-200 ° C, the reaction speed is relatively fast, the yield is relatively high, and the side reaction phenomenon is not obvious; when T = 200-210 ° C and T = 210-220 ° C, the side reaction phenomenon is very obvious, as shown by the convex bag-shaped broad peak in the middle of the figure. Comparing the reaction conditions in the temperature range, it can be seen that the temperature at T = 200 ° C is the best reaction temperature.

[0060] Effect of Boric Acid Addition Amount on Yield of 1,4-Dihydroxyanthraquinone

[0061] The yield of 1,4-dihydroxyanthraquinone under different addition amounts of boric acid was investigated, and the specific experimental data are shown in Table 3:

[0062] Table 3 Effect of boric acid addition on 1,4-dihydroxyanthraquinone yield

[0063] Serial number Boric acid feeding amount m / g Yield W NO.1 0.20 0.56 NO.2 0.40 0.64 NO.3 0.60 0.75 NO.4 0.80 0.76 NO.5 1.00 0.75

[0064] From Table 3, we can get Figure 6 The trend diagram shown in Table 3 and Figure 6 From the analysis of experimental data, it can be seen that when 9.20 g of 98% concentrated sulfuric acid is fixed and the amount of boric acid added is changed, the relative yield of the product increases with the increase in the amount of boric acid added. When the amount added is increased from 0.6 g to 1.0 g, the yield almost stops increasing and the catalysis reaches equilibrium. Therefore, in this application, 1 g of boric acid is selected to be added.

[0065] Effect of sulfuric acid concentration on the yield of 1,4-dihydroxyanthraquinone:

[0066] In the chlorine-to-hydroxyl reaction, the relative proportion of sulfuric acid has a great influence on the reaction conversion rate. Sulfuric acid is a strong oxidant and also appears in the reaction as a dehydrating agent. The amount of boric acid added was fixed, and only the sulfuric acid concentration was changed under the same reaction conditions. Further research on the reaction yield was conducted. Figure 7 The figures show the extent of the side reaction of 1,4-dihydroxyanthraquinone under different concentrations of sulfuric acid. Figure 7It can be found that when the sulfuric acid concentration is H2SO4:H2O = 80:20, the catalytic reaction rate of boric acid is relatively slow, and the time required to reach the same yield is long; when the sulfuric acid concentration is H2SO4:H2O = 90:10, within the same reaction time, the yield reached by the reaction is relatively high and the side reactions are relatively few; when the sulfuric acid concentration is H2SO4:H2O = 96:4, the yield is even higher within the same time, the reaction rate is fast, and the side reaction products are also relatively few; when the sulfuric acid concentration is further increased to H2SO4:H2O = 98:2, although the reaction is very fast, the by-products begin to increase; when the sulfuric acid concentration is H2SO4:H2O = 105:0, the raw materials tend to undergo sulfonation side reactions, and sulfur trioxide in sulfuric acid is volatile and easily causes environmental pollution. Sulfur trioxide gas forms asbestos-like crystals when cooled, blocking the device pipeline and easily causing production accidents. As Figure 7 shown, with the extension of time, almost no main product is formed. Therefore, the sulfuric acid concentration has a great influence on this reaction. At different sulfuric acid concentrations, the yields of 1,4-dihydroxyanthraquinone are shown in Table 4 below:

[0067] Table 4 Influence of sulfuric acid concentration on the yield of 1,4-dihydroxyanthraquinone

[0068] Serial number Sulfuric acid concentration ω Yield W NO.1 1.05 0.47 NO.2 1.00 0.76 NO.3 0.96 0.80 NO.4 0.90 0.71 NO.5 0.8 0.65

[0069] Using origin to draw a graph, the trend graph of the influence of sulfuric acid concentration on the yield of 1,4-dihydroxyanthraquinone is as Figure 8 shown.

[0070] From Table 4 and Figure 8 it can be seen that during the process of increasing the sulfuric acid concentration from 0.8 to 1.05, the degree of sulfonation side reaction intensifies, and around 0.96, the yield of 1,4-dihydroxyanthraquinone is the highest. Therefore, the relative sulfuric acid concentration of 0.96 is selected as the optimal concentration.

[0071] A clean production method for the 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs provided by the present invention uses steps of feeding materials, reacting, hydrolyzing, suction filtering, and drying to produce 1,4-dihydroxyanthraquinone products. And the mother liquor wastewater generated in the suction filtering step is successively subjected to cooling crystallization, resin adsorption, phthalic acid desorption, resin regeneration, and phthalic acid refining treatment to obtain phthalic acid. After drying the phthalic acid, it is recycled to the synthesis of the 1,4-dihydroxyanthraquinone pharmaceutical intermediate, and the filtrate is incorporated into the mother liquor wastewater of the next batch of synthesis for treatment. It can realize the resource recovery and utilization of the mother liquor wastewater and the clean production of 1,4-dihydroxyanthraquinone, effectively saving resources. The discharge amount of the mother liquor wastewater can be reduced from 25000 kg / ton to 1130 kg / ton.

[0072] Other embodiments of the present application will be readily contemplated by those skilled in the art upon consideration of the specification and practice of the application disclosed herein. The present application is intended to cover any variations, uses, or adaptations of the present application, which follow the general principles of the present application and include the common general knowledge or conventional technical means in the technical field disclosed by the present application. The specification and examples are only considered to be exemplary, and the true scope of the present application is pointed out by the claims.

[0073] It should be understood that the present application is not limited to the exact structures described above and shown in the drawings, and various modifications and changes can be made without departing from its scope. The embodiments of the present application described above do not constitute a limitation on the protection scope of the present application.

Claims

1. A clean production method for 1,4-dihydroxyanthraquinone pharmaceutical intermediates for anti-tumor drugs, characterized in that: include: Feeding: Pour 9.20 g of 96% sulfuric acid into the reactor and stir at 120 r / min, slowly add 1.00 g of boric acid and 3.88 g of phthalic anhydride in sequence, gradually heat the reactor to 120°C using a high and low temperature all-in-one machine, and after the materials are completely dissolved, begin to drop 1.60 g of p-chlorophenol; Reaction: After the feeding is completed, the reactor is gradually heated to 50°C by the high and low temperature integrated machine, and the temperature is kept for 1 hour; the high and low temperature integrated machine is adjusted for the second time, the reactor is gradually heated to 180°C, and the temperature is kept for 2 hours; the high and low temperature integrated machine is adjusted for the third time, the reactor is gradually heated to 200°C, and the temperature is kept for 8-10 minutes to obtain a condensation liquid; Hydrolysis: Add 36.5g of water into the hydrolysis tank and stir, slowly add the condensation liquid into the water, stir and keep warm at 95-105°C for 4h, then the crude 1,4-dihydroxyanthraquinone crystals can be crystallized in hot water; Filtration: adding the hydrolyzate at 95-105° C. into a vacuum filtration device in batches, collecting the crude 1,4-dihydroxyanthraquinone crystals and mother liquor wastewater, washing the crude 1,4-dihydroxyanthraquinone crystals with 85° C. hot water, and then filtering again to obtain 1,4-dihydroxyanthraquinone crystals; Drying: adding the 1,4-dihydroxyanthraquinone crystals into a drying kettle, performing negative pressure drying at a temperature of 120-130° C. and a pressure of -0.07 MPa, and cooling to below 50° C. after drying to obtain a 1,4-dihydroxyanthraquinone product; Cooling crystallization: cooling the mother liquor wastewater and then performing cooling crystallization, filtering to obtain filtrate I and filter cake I, wherein filter cake I is crude phthalic acid; Resin adsorption: The collected filtrate I is injected from the upper end of an adsorption column filled with 100 ml of different types of styrene macroporous resins for adsorption, and different resin volume multiples are adsorbed, and the adsorbed liquid is collected; Phthalic acid desorption and resin regeneration: blow dry the saturated resin, and inject different adsorption liquids from the bottom of the adsorption column for backwash desorption; After desorption, the mixture was blown dry and the alkaline desorption solution was collected; Phthalic acid purification: the alkaline desorption liquid is used as bottom water, added to filter cake I, heated, adjusted to pH = 8-9 with 30% sodium hydroxide solution and filtered, the filtrate is collected and adjusted to pH = 2-7 ​​with adsorption liquid, cooled to below 15°C, filtered to obtain filtrate II and filter cake II, filter cake II is phthalic acid, the filter cake II is dried and recycled, and the filtrate II is incorporated into the next batch of synthetic mother liquor wastewater for treatment.

2. The clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs according to claim 1, characterized in that: In the phthalic acid desorption and resin regeneration step, after collecting the alkaline desorption liquid, it also includes: injecting hot water from the bottom of the adsorption column for backwashing, and after washing, sending the collected backwashing liquid to the resin adsorption step for adsorption treatment again.

3. The clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs according to claim 1, characterized in that: The HCL gas produced in the reaction step is passed into a water washing tank and dissolved in 2.5 g of water to generate dilute hydrochloric acid.

4. The clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs according to claim 1, characterized in that: In the feeding step, the increase in temperature of the high and low temperature integrated machine at a single time is ≤30°C.

5. The clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs according to claim 1, characterized in that: In the resin adsorption step, after collecting the adsorption liquid, the method further includes testing the COD content and sulfuric acid acidity of the adsorption liquid and collecting the test data.

6. The clean production method of 1,4-dihydroxyanthraquinone pharmaceutical intermediate for anti-tumor drugs according to claim 1, characterized in that: The washing water obtained in the suction filtration step is recycled to the hydrolysis step.

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