Preparation method of efficient fluorescent marker

Abstract

The invention relates to a preparation method of an efficient fluorescent marker, which comprises the following steps: taking resorcinol and phthalic anhydride as starting materials, carrying out Friedel-Crafts acylation reaction in 80% sulfuric acid, carrying out Michael addition reaction, and dehydrating to generate fluorescein YYG-1; carrying out acylation reaction on the YYG-1 in acetic anhydride to obtain a diacetyl product YYG-2; hydrolyzing the YYG-2 with sodium methoxide to obtain fluorescein YYG-3; and carrying out alkalization and salification on the YYG-3 to prepare the sodium fluorescein YYG. According to the synthetic route, the high yield of the fluorescein sodium is realized by controlling the pH range in the hydrolysis step and the use amount of sodium hydroxide in the alkalization step, and the fluorescein sodium is high in purity, stable in quality and simple to operate.

Description

Technical Field

[0001] This invention belongs to the field of chemical production processes and relates to a method for preparing a highly efficient fluorescent label. By optimizing reaction conditions and process flow, the efficient preparation of sodium fluorescein is achieved. This method can improve the production yield and purity of sodium fluorescein, providing technical support for the industrial production of this compound. Background Technology

[0002] Fluorescein sodium, a highly efficient fluorescent label, is chemically named 9-(o-carboxyphenyl)-6-hydroxy-3H-xanthon-3-one disodium salt. It is used to treat and diagnose corneal injuries, ulcers, and foreign bodies, as well as for fundus angiography and circulation time measurement. It is also used for intraoperative visualization of the gallbladder and bile ducts, and as an adjunct to the diagnosis of tuberculous meningitis.

[0003] CN101270124B discloses a blend of fluorescein and sodium carbonate, which is dissolved in water on an evaporating pan, then heated to evaporate the water, vacuum dried, and ground to obtain sodium fluorescein. Water evaporation is a time-consuming and energy-intensive process, and the dried solid is not crystalline. When sodium fluorescein is separated from the aqueous solution, the precipitate is very sticky or tarry, sometimes brittle, requiring mechanical effort, and is difficult to filter and handle. Furthermore, it is difficult to remove moisture from the separating material, and extensive drying at high temperatures is required.

[0004] CN101628907B discloses a purification method in which sodium fluorescein is dissolved in an organic solvent, then treated with charcoal to achieve a pH of 8.7, and then the solution is concentrated by drying at 105°C. Drying at higher temperatures increases costs, the solid is not in crystalline form, multiple solvents are used for treatment, and sodium fluorescein is a hygroscopic material, highly soluble in aqueous solutions.

[0005] CN103288844A discloses a method for preparing fluorescein from resorcinol and phthalic anhydride. The fluorescent yellow solid is purified by acid and alkali treatment, then treated in water with sodium bicarbonate solution, and finally the water is evaporated to obtain the solid. However, the acid and alkali purification process involves additional wastewater treatment, making it very difficult or impossible to separate crystalline sodium fluorescein from an aqueous or water-containing solution.

[0006] WO2023037158A1 discloses a one-step method for preparing sodium fluorescein, in which diacetylfluorescein is hydrolyzed in methanol solvent under sodium hydroxide conditions, and then acetone is added to crystallize and obtain sodium salt. However, the crystallization process is very difficult, and crystals could not be precipitated by crystallization with acetone.

[0007] Therefore, the production process of sodium fluorescein still has some problems, such as unstable reaction conditions, difficulty in crystallization, low purity, and high cost. There is an urgent need to further study and improve the control of key processes, in order to provide a preparation method for sodium fluorescein that is different from the previous preparation process. Summary of the Invention

[0008] The technical problem solved by this application is to provide a method for preparing highly efficient fluorescent markers.

[0009] The method for preparing highly efficient fluorescent labels in this application includes the following steps:

[0010] (1) Resorcinol and phthalic anhydride are used as starting materials. The reaction proceeds under acidic conditions through Friedel-Crafts acylation, Michael addition, and dehydration to generate fluorescein (YYG-1).

[0011] (2) YYG-1 was acylated with acetic anhydride to prepare diacetyl product (YYG-2);

[0012] (3) YYG-2 was hydrolyzed under alkaline conditions and then acidified to obtain fluorescein (YYG-3);

[0013] (4) Sodium fluorescein (YYG) was prepared by converting YYG-3 into sodium salt.

[0014] In one embodiment of the present invention, the method for preparing a highly efficient fluorescent label includes the following steps:

[0015] Step (1): Phthalic anhydride and resorcinol are reacted by heating in 80% sulfuric acid to 130℃~140℃. After the reaction is completed, purified water is added, the temperature is lowered to crystallize, and the mixture is filtered and dried to obtain YYG-1.

[0016] Step (2): YYG-1 was heated to 120℃~130℃ under the condition that the amount of acetic anhydride as the acylation reagent was 2.5-3.5 eq, and then cooled to crystallize to obtain YYG-2.

[0017] Step (3): YYG-2 was reacted by adding a methanol solution of sodium methoxide dropwise to methanol solvent, acetic acid was added, and the pH was adjusted to 3-4 with hydrochloric acid for the first time. Crystallization occurred, and the solid was filtered and dried. The obtained solid was added with purified water, and the pH was adjusted to 1-3 with hydrochloric acid for the second time. Then it was heated to 95℃-100℃ and stirred for 15 minutes. The temperature was lowered to 15℃-25℃ to crystallize. The solid was filtered and dried to obtain YYG-3.

[0018] Step (4): Dissolve sodium hydroxide in purified water, add YYG-3 at 15℃~30℃, stir for 30min, filter, dry the residue, and obtain the finished product YYG fluorescein sodium.

[0019] In one embodiment, in step (1), the ratio of phthalic anhydride to resorcinol is 1:1.8 to 1:3.

[0020] In one embodiment, in step (1), the ratio of phthalic anhydride to resorcinol is 1:3.

[0021] In one implementation, in step (1), the amount of purified water used is 16V-18V.

[0022] In one implementation, in step (1), the water addition process maintains the system temperature at no less than 90°C.

[0023] In one implementation, in step (2), the reaction time is 2h to 5h, preferably 2h to 3h.

[0024] In one implementation, in step (2), the temperature is heated to 120°C.

[0025] In one embodiment, in step (3), the sodium methoxide feed equivalent is 3.0 eq to 3.5 eq.

[0026] In one implementation, in step (3), the sodium methoxide feed equivalent is 3.5 eq.

[0027] In one implementation, in step (3), the second pH value is adjusted to 1-2.

[0028] In one implementation, in step (3), the amount of purified water used is >15V, preferably 18V.

[0029] In one implementation, the purity of fluorescein YYG-3 in step (3) is greater than 99.0%.

[0030] In one implementation, the purity of fluorescein YYG-3 in step (3) is greater than 99.5%.

[0031] In one embodiment, in step (4), the amount of sodium hydroxide added is 1.0 eq to 2.5 eq.

[0032] In one embodiment, in step (4), the amount of sodium hydroxide fed is 2.0 eq.

[0033] In one implementation, in step (4), the amount of purified water used is 1.5v.

[0034] In one implementation, in step (4), the drying is vacuum drying at a temperature of 80°C.

[0035] In one embodiment, the purity of sodium fluorescein is 99.5%.

[0036] In one embodiment, the purity of sodium fluorescein is greater than 99.8%.

[0037] In one embodiment, the purity of sodium fluorescein is greater than 99.9%.

[0038] In another embodiment, the prepared sodium fluorescein does not contain more than 0.05% of any related substances.

[0039] In one embodiment, the prepared sodium fluorescein does not contain more than 0.01% of any related substances.

[0040] Compared with the prior art, the present invention has the following beneficial effects: In the preparation process of sodium fluorescein, the reaction conditions of key preparation processes are improved: (1) In the hydrolysis stage, by controlling the pH adjustment twice in the hydrolysis step, a high-purity product is obtained. This improvement promotes the high purity of sodium fluorescein, achieving a purity of over 99.5%, and even up to 99.9%; (2) Controlling the amount of sodium hydroxide reagent in the alkalization step to limit it to a highly efficient range. This improvement effectively improves the yield of sodium fluorescein, with a stable yield of over 95%; (3) Through the synergistic improvement of the above two aspects, high purity and high yield of sodium fluorescein are successfully achieved. This comprehensive optimization strategy ultimately achieves both high purity and high yield of sodium fluorescein. Detailed Implementation

[0041] The technical solutions in the embodiments of this application will be clearly described below with reference to the examples. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0042] The method for preparing highly efficient fluorescent labels in this application includes the following steps:

[0043] (1) Resorcinol and phthalic anhydride are used as starting materials. The reaction proceeds under acidic conditions through Friedel-Crafts acylation, Michael addition, and dehydration to generate fluorescein (YYG-1).

[0044] (2) YYG-1 was acylated with acetic anhydride to prepare diacetyl product (YYG-2);

[0045] (3) YYG-2 was hydrolyzed under alkaline conditions and then acidified to obtain fluorescein (YYG-3);

[0046] (4) Sodium fluorescein (YYG) was prepared by converting YYG-3 into sodium salt.

[0047] Specifically, the present invention is implemented in the following manner.

[0048] Step 1: Resorcinol and phthalic anhydride are used as starting materials. Under acidic conditions, they undergo Friedel-Crafts acylation, Michael addition reaction, and dehydration to generate fluorescein (YYG-1).

[0049]

[0050] Specifically, phthalic anhydride (YYG-SM-A) and resorcinol (YYG-SM-B) are reacted in an 80% sulfuric acid aqueous solution by heating to 130℃~140℃. After the reaction is complete, purified water is added, and the mixture is cooled to crystallize. The crystals are then filtered, the solid is collected, and dried to obtain solid YYG-1.

[0051] In one embodiment of this step, the feed ratio of phthalic anhydride to resorcinol is greater than 1:1.8. In a specific embodiment of the present invention, the feed ratio of phthalic anhydride to resorcinol is from 1:1.8 to 1:3. Preferably, the feed ratio of phthalic anhydride to resorcinol can be 1:1.8, 1:2.0, 1:2.2, 1:2.5, 1:2.8, or 1:3. However, it is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0052] In one embodiment, the purified water volume is greater than 10V, preferably 16V, 17V, or 18V. Too little water results in a low yield, while too much increases equipment requirements. However, this is not limited to the listed values; other unlisted values ​​within this range also apply.

[0053] In one embodiment, the process of adding purified water is carried out at a temperature of not less than 90°C, which can prevent the system from clumping and solve the problem of material discharge blockage.

[0054] Step 2: YYG-1 undergoes an acylation reaction with acetic anhydride to obtain the diacetyl product (YYG-2).

[0055]

[0056] Specifically:

[0057] YYG-1 was reacted with acetic anhydride (an acylation reagent) at a ratio of 1:2.5-3.5, and then cooled to crystallize to obtain YYG-2.

[0058] Preferably, the YYG-1 / acetic anhydride feed ratio is 1 / 3.5, and the reaction time is 3 hours. When the YYG-1 / acetic anhydride ratio is 1 / 2.5, a relatively large amount of YYG-1 remains. However, when the amount of acetic anhydride is increased to 3.5 eq, HPLC monitoring after 3 hours shows that the remaining amount of YYG-1 is less than 0.1%, indicating an ideal reaction effect. Excessive use of acetic anhydride increases costs. Extending the reaction time to 5 hours does not significantly change the purity of the main peak, but after 7 hours, the purity of the main peak decreases noticeably.

[0059] In one embodiment, when the reaction temperature is 80–100°C, undissolved YYG-1 solid is detected in the reaction solution, indicating no reaction or an unsatisfactory reaction. In another embodiment, the reaction temperature is 120°C, the solid completely dissolves in the system, and after 2 hours of reaction, 0.1% of the raw material YYG-1 remains.

[0060] Step 3: YYG-2 is hydrolyzed under alkaline conditions and then acidified to obtain fluorescein (YYG-3).

[0061]

[0062] Specifically:

[0063] YYG-2 was reacted by adding a methanol solution of sodium methoxide dropwise to 2.5V methanol as solvent. Acetic acid was added, and the pH was adjusted to 3-4 with hydrochloric acid for the first time. Crystallization occurred, and the solid was filtered and dried. The obtained solid was added with purified water, and the pH was adjusted to 1-3 with hydrochloric acid for the second time. Then, it was heated to 95℃-100℃ and stirred for 15 minutes. The temperature was then lowered to 15℃-25℃ to crystallize. The solid was filtered and dried to obtain YYG-3.

[0064] The inventors further discovered that, in the process of preparing YYG-3, controlling the amount of sodium methoxide as feed, adjusting the pH value within a certain range, and using water to slurry can reduce the impurity content and improve the yield and purity of YYG-3 in this step.

[0065] Furthermore, this step allows for control of the sodium methoxide feed equivalent to improve yield and reduce impurity content. When the equivalent is insufficient, YYG-2 hydrolysis is incomplete, resulting in a lower yield and increased impurities. When the sodium methoxide feed equivalent is 5.0 eq, the impurity peaks are larger, increasing the difficulty of subsequent purification. Comparing 3.0 eq and 3.5 eq, the purity and the amount of unknown impurities are not significantly different. From a yield perspective, a sodium methoxide feed equivalent of 3.0 eq yields 78%; a sodium methoxide feed equivalent of 3.5 eq yields over 90%, even exceeding 95%. Therefore, a sodium methoxide feed equivalent of 3.5 eq is preferred.

[0066] In one implementation, the pH value is adjusted to approximately 3-4, such as 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, etc.

[0067] In one embodiment, the pH value is adjusted a second time by about 1 to 2, preferably 1.0, 1.2, 1.5, 1.8, 2.0, etc.

[0068] During this preparation step, inorganic salts are generated. Without water washing, a large amount of inorganic salts may remain, affecting the quality of the finished product. Therefore, further, water slurrying is used to improve the yield and purity of YYG-3. Preferably, the amount of purified water used is >15V, such as 16V, 17V, 18V, etc.; more preferably, the amount of purified water used is 18V.

[0069] Preferably, the purity of YYG-3 is greater than 99.5%.

[0070] Preferably, the purity of YYG-3 is greater than 99.8%.

[0071] Preferably, the yield of YYG-3 is 70%-85%.

[0072] Preferably, the yield of YYG-3 is 75%-80%.

[0073] Step 4: Prepare sodium fluorescein (YYG) by converting YYG-3 into its sodium salt.

[0074]

[0075] Specifically:

[0076] Option 1. Dissolve sodium hydroxide reagent in purified water, add YYG-3 at 15℃~30℃, stir for 30min, filter, and dry the residue to obtain the finished sodium fluorescein YYG.

[0077] Option 2. Fluorescein (YYG-3) reacts with sodium methoxide reagent in methanol to form a sodium salt, and the solid is crystallized out in acetone to obtain the finished product YYG fluorescein sodium.

[0078] The inventors discovered that, under scheme 2, when multiple batches were used to form sodium salt in methanol with fluorescein (YYG-3) and sodium methoxide reagent, followed by acetone crystallization, solids could be successfully precipitated. However, the residual methanol and acetone solvents in the products exceeded the limits.

[0079] The inventors further discovered that the process of preparing YYG in Scheme 1 can ensure that the step is operable for scale-up pilot production, does not use organic solvents, does not cause solvent residue problems, and reduces production costs and organic waste liquid treatment.

[0080] In one embodiment, the sodium hydroxide feed equivalent is 1.0 eq-2.5 eq; preferably, the sodium hydroxide feed equivalent is 1.0 eq, 1.5 eq, or 2.0 eq. Insufficient equivalent may cause the product pH to be too low and unqualified; excessive equivalent may cause the pH to exceed the limit. Preferably, the pH is about 8.0.

[0081] In one embodiment, the preferred amount of purified water is 1.5 v. Too little water results in a viscous solution that cannot be filtered or transferred, while too much water increases the drying time.

[0082] In one embodiment, vacuum drying is preferred, with a drying temperature of 80°C. Excessively high temperatures increase equipment requirements and energy consumption.

[0083] In one embodiment, the drying temperature is preferably >100°C, such as 105°C, 110°C, 115°C or 120°C.

[0084] In one embodiment, preferred option 1 is as follows: Sodium hydroxide is dissolved in 1.5V water, YYG-3 is added, and the mixture is stirred until clear. The solution is concentrated under reduced pressure to remove 1 / 3 of the purified water. The remaining substance is poured into a drying tray while hot and dried under vacuum at 80°C to obtain YYG.

[0085] Preferably, the purity of sodium fluorescein is 99.5%.

[0086] Preferably, the purity of sodium fluorescein is greater than 99.8%.

[0087] Preferably, the purity of sodium fluorescein is greater than 99.9%.

[0088] Preferably, the prepared sodium fluorescein does not contain more than 0.05% of any related substances.

[0089] Preferably, the prepared sodium fluorescein does not contain more than 0.01% of any related substances.

[0090] Preferably, the yield of sodium fluorescein is greater than 90%, or even greater than 95%.

[0091] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and are not used to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and are not limited in number; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship. The terms "about" or "approximately" should have the meaning of within 10%, more preferably within 5%, of a given value or range. It should be understood that the numerical values ​​listed in this application include those values ​​as well as other unlisted values ​​within the numerical range. Purity is determined by high-performance liquid chromatography (HPLC) in this application.

[0092] Example 1:

[0093] Step (1):

[0094]

[0095] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0096] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0097] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0098] Step (2):

[0099] Material Name molecular weight Feed quantity (kg) Number of moles (mol) Equivalent ratio YYG-1 332.31 2.20 6.62 1.0 Acetic anhydride 102.09 2.36 23.17 3.5 Acetic acid - 1.10 - - acetone - 3.52 - -

[0100] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0101] Step (3)

[0102] Material Name molecular weight Feed quantity (kg) Number of moles (mol) Equivalent ratio YYG-2 416.38 2.00 4.81 1.0 Sodium methoxide 54.02 0.91 16.8 3.5 Acetic acid 60.05 1.15 19.21 4.0 Methanol① - 4.00 - - Methanol ② - 4.00 - - Purified water - 24.00 - - hydrochloric acid - 0.40 - -

[0103] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0104] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0105] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0106] Step (4)

[0107] Material Name molecular weight Feed quantity (kg) Number of moles (mol) Equivalent ratio YYG-3 332.31 1.10 3.31 1.0 Sodium hydroxide 40.00 0.265 6.62 2.0 Purified water - 1.65 - -

[0108] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and vacuum dry at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.18 kg of brownish-red solid. Yield: 97.5%.

[0109] Example 2:

[0110] Step (1):

[0111] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0112] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0113] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0114] Step (2):

[0115] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0116] Step (3)

[0117] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0118] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃ to a methanol solution of 0.91 kg sodium methoxide (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0119] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 2, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0120] Step (4)

[0121] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and dry it under vacuum at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.25 kg of brownish-red solid. Yield: 103.3%.

[0122] Example 3:

[0123] Step (1):

[0124] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0125] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0126] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0127] Step (2):

[0128] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0129] Step (3)

[0130] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0131] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃ to a methanol solution of 0.91 kg of sodium methoxide (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 4 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0132] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0133] Step (4)

[0134] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and dry it under vacuum at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.17 kg of brownish-red solid. Yield: 96.3%.

[0135] Example 3:

[0136] Step (1):

[0137] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0138] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0139] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0140] Step (2):

[0141] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0142] Step (3)

[0143] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0144] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃ to a methanol solution of 0.91 kg sodium methoxide (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.8 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0145] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 2, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0146] Step (4)

[0147] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and dry it under vacuum at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.172 kg of brownish-red solid. Yield: 96.8%.

[0148] Example 5:

[0149] Step (1):

[0150] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0151] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0152] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0153] Step (2):

[0154] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0155] Step (3)

[0156] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0157] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0158] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0159] Step (4)

[0160] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.133 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and vacuum dry at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.15 kg of brownish-red solid. Yield: 95%.

[0161] Example 6:

[0162] Step (1):

[0163] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0164] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0165] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0166] Step (2):

[0167] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0168] Step (3)

[0169] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0170] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0171] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0172] Step (4)

[0173] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.33 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and vacuum dry at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.15 kg of brownish-red solid. Yield: 95%.

[0174] Comparative Example 1:

[0175] Step (1):

[0176] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0177] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0178] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0179] Step (2):

[0180] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0181] Step (3)

[0182] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0183] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0184] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0185] Step (4)

[0186] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.212 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and vacuum dry at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 0.85 kg of brownish-red solid. Yield: 70%.

[0187] Comparative Example 2:

[0188] Step (1):

[0189] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0190] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0191] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0192] Step (2):

[0193] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0194] Step (3)

[0195] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0196] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0197] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0198] Step (4)

[0199] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.398 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and vacuum dry at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 0.91 kg of brownish-red solid. Yield: 75.3%.

[0200] Comparative Example 3:

[0201] Step (1):

[0202] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0203] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0204] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0205] Step (2):

[0206] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0207] Step (3)

[0208] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0209] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, followed by the addition of 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 4.2 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0210] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0211] Step (4)

[0212] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and vacuum dry at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.02 kg of brownish-red solid. Yield: 85%.

[0213] Comparative Example 4:

[0214] Step (1):

[0215] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0216] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0217] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0218] Step (2):

[0219] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0220] Step (3)

[0221] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0222] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0223] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 2.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0224] Step (4)

[0225] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and dry it under vacuum at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 1.03 kg of brownish-red solid. Yield: 85.8%.

[0226] Comparative Example 5:

[0227] Step (1):

[0228] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0229] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0230] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0231] Step (2):

[0232] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0233] Step (3)

[0234] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0235] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, followed by the addition of 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 4.2 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0236] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 1.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry it under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. 1.26 kg of brown solid was collected, yield: 79.3%.

[0237] Step (4)

[0238] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.398 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and dry it under vacuum at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 0.89 kg of brownish-red solid. Yield: 73.7%.

[0239] Comparative Example 6:

[0240] Step (1):

[0241] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0242] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0243] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0244] Step (2):

[0245] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystal was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. YYG-2 (2.01 kg) was collected as a yellow solid, with a yield of 73.1%.

[0246] Step (3)

[0247] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0248] 2.00 kg of YYG-2 was added dropwise at a controlled temperature of 15℃~25℃, along with 0.91 kg of sodium methoxide in methanol (4.00 kg). After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The concentration of YYG-2 was less than 0.1%. The reaction was then completed. 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. The mixture was then filtered and dried in a forced-air dryer at 50℃ for 21 hours. 1.67 kg of orange-red solid was obtained.

[0249] Add 24.00 kg of purified water and 1.6 kg of solid to a 50 L glass reactor, start stirring, add concentrated hydrochloric acid (about 0.40 kg) to adjust the pH to 0.5, then heat the system to 95℃~100℃ and stir for 15 minutes, cool to 15℃~25℃ and stir for 1 hour, filter, wash the filter cake with 10.00 kg of water, dry under vacuum, and dry the obtained solid at 60℃ for 8 hours. Take 1.0 g and test it with a rapid moisture analyzer, and the moisture content was found to be 0.17%. The yield was 1.26 kg of brown solid YYG-3, with a yield of 79.3%.

[0250] Step (4)

[0251] Add 1.65 kg of purified water to a 5 L reaction flask and stir. Maintain the temperature at 15℃~20℃. Add 0.265 kg of sodium hydroxide solid and stir for 30 minutes. Weigh out 1.10 kg of YYG-3 and add it to the solution. Continue stirring at 15℃~20℃ for 30 minutes. Filter the solution using a plate filter (0.2 μm filter membrane) into a 50 L glass reactor in a clean area. After filtration, transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure at 60℃ (vacuum degree -0.095 MPa) to remove one-third of the water. While still hot, place the remaining residue in a drying tray and dry it under vacuum at 80℃. Take 1.0 g of the residue during the process and test it with a rapid moisture analyzer. When the loss on drying is less than 10.0%, collect 0.98 kg of brownish-red solid. Yield: 81.2%.

[0252] Comparative Example 7:

[0253] Step (1):

[0254] Add 2.23 kg of resorcinol and 1.00 kg of phthalic anhydride to a 5 L three-necked flask and stir. Slowly add 80% sulfuric acid (1.03 kg sulfuric acid / 0.14 kg purified water) to the reaction flask and heat to 130-140 °C for 3 h. Send the reaction solution to HPLC for analysis. The reaction is considered complete when the remaining amount of YYG-SM-A is less than 2.0%.

[0255] Add 18.00 kg of purified water to a 20 L reactor and heat it to 90–100 °C.

[0256] The system was slowly poured into a 20L reactor (maintaining an internal temperature of no less than 90℃ throughout the process). After the addition was complete, the mixture was stirred at 90-100℃ for 30 minutes, then cooled to 15-25℃ and stirred for 2 hours. The mixture was then filtered and washed with 5.0 kg of purified water to obtain a brownish-red solid (wet product). The solid was vacuum dried at 60℃ under a vacuum of ≤-0.085 MPa for 12 hours. A sample was taken to determine the rapid drying loss (measured at 105℃ for 5 minutes), which was less than 0.5%. 2.28 kg of the brownish-red solid YYG-1 was obtained, with a yield of 99.3%.

[0257] Step (2):

[0258] 1.10 kg of acetic acid was added to a 50 L glass reactor, and stirring was started. 2.20 kg of YYG-1 was weighed and added to the 50 L glass reactor, followed by 2.36 kg of acetic anhydride. The mixture was stirred and heated to 120℃~130℃ and maintained at this temperature for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The reaction was considered complete when the remaining amount of YYG-1 was less than 0.1%. The system was then cooled to 60℃~70℃, and 3.52 kg of acetone was added dropwise at a uniform rate. After the addition was complete, the mixture was stirred for 30 minutes, and then cooled further to 0℃~5℃ with stirring for 3 hours to allow crystallization. The crystals were filtered and washed with 2.00 kg of ice-cold acetone. After drying for 8 hours, 1.0 g of the crystals was analyzed using a rapid moisture analyzer, and the moisture content was found to be less than 0.5%. 2.01 kg of a yellow solid was collected, with a yield of 73.1%.

[0259] Step (3)

[0260] Add 4.00 kg of methanol① to a 50 L glass reactor, start stirring, and add...

[0261] 2.00 kg of YYG-2 was added dropwise to a 4.00 kg solution of sodium methoxide in methanol (solution ②) at a controlled temperature of 15℃~25℃. After the addition was complete, the reaction was maintained at 15℃~25℃ for 3 hours. A sample of the reaction solution was sent for HPLC analysis. The YYG-2 concentration was less than 0.1%. After the reaction was completed, 1.20 kg of acetic acid was added dropwise, and the pH was adjusted to 3.5 with concentrated hydrochloric acid. The mixture was stirred and crystallized for 3 hours. After filtration, the mixture was dried in a forced-air dryer at 50℃ for 21 hours, yielding 1.67 kg of orange-red solid. The residue on ignition was 21.5%. This indicates that there was a large amount of inorganic salt remaining, and the impurity content was high, which is not conducive to subsequent processes.

[0262] In summary, the effects of pH within a specific range during YYG-3 preparation and the amount of NaOH during YYG preparation on impurities and yield are shown in Table A:

[0263]

[0264] Therefore, it can be seen that in the process parameters of each step in Examples 1-6 above, there are no harsh reaction conditions, no highly toxic reagents, no special equipment requirements, and no high-risk operations. The reaction conditions of the entire preparation process are mild, and the generated "three wastes" are easy to treat, making it suitable for industrial-scale production.

[0265] The embodiments of this application have been described above, but this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for preparing a highly efficient fluorescent label, characterized in that, Includes the following steps: (1): Phthalic anhydride and resorcinol were reacted by heating in 80% sulfuric acid to 130℃~140℃. After the reaction was completed, purified water was added, the temperature was lowered to crystallize, and the mixture was filtered and dried to obtain fluorescein (YYG-1). (2): YYG-1 from step (1) was heated to 120℃~130℃ under the condition that the amount of acetic anhydride acylation reagent added was 2.5-3.5 eq, and then cooled down to crystallize and obtain diacetylfluorescein (YYG-2). (3): YYG-2 from step (2) was reacted by adding a methanol solution of sodium methoxide dropwise to methanol solvent, acetic acid was added, the pH was adjusted to 3-4 with hydrochloric acid, crystallization occurred, the solid was filtered and dried, the pH was adjusted to 1-3 with purified water at 18.0V, then heated to 95℃-100℃ and stirred for 15 minutes, cooled to 15℃-25℃ to crystallize, filtered and dried to obtain fluorescein (YYG-3); (4): Dissolve sodium hydroxide in purified water, add YYG-3 from step (3) at 15℃~30℃, stir for 30min, filter, dry the residue to obtain sodium fluorescein YYG.

2. The preparation method according to claim 1, characterized in that, In step (1), the ratio of phthalic anhydride to resorcinol is 1:1.8 to 1:3; the amount of purified water used is 16V-18V.

3. The preparation method according to claim 1, characterized in that, In step (1), the water addition process should maintain the system temperature at no less than 90°C.

4. The preparation method according to claim 1, characterized in that, The feed ratio of YYG-1 / acetic anhydride in step (2) is 1 / 3.

5.

5. The preparation method according to claim 1, characterized in that, In step (3), the sodium methoxide feed equivalent is 3.0 eq to 3.5 eq, preferably 3.5 eq.

6. The preparation method according to claim 1, characterized in that, In step (3), the pH value is adjusted to 1-2 for the second time.

7. The preparation method according to claim 1, characterized in that, The amount of purified water used in step (3) is >15V, preferably 18V.

8. The preparation method according to claim 1, characterized in that, The amount of purified water used in step (4) is 1.5V.

9. The preparation method according to claim 1, characterized in that, The drying in step (4) is vacuum drying at a temperature of 80°C.

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