Synthesis and purification method of trihydroxy phenol compound

Abstract

The invention discloses a synthesis and purification method of a trihydroxy phenol compound, which comprises the following steps: dissolving a crude product of resorcinol or a derivative thereof in methanol to obtain a solution, dropwise adding a methanol solution of p-toluenesulfonic acid and a ketone compound into the solution, and carrying out catalytic reaction at 50-70 DEG C to obtain a reaction solution; dropwise adding the obtained reaction liquid into deionized water at the temperature of 0-5 DEG C at the speed of 1-3 mL / min, stirring to separate out a white solid, and performing suction filtration to obtain a crude product; dissolving the crude product in ethyl acetate, adding column chromatography silica gel powder, stirring and adsorbing, separating supernate, and concentrating; and dissolving the concentrated solution in a mixed solvent of methanol and water, heating to 60-65 DEG C, dissolving, cooling to below 5 DEG C at a rate gradient of less than or equal to 0.5 DEG C / min, crystallizing, filtering, and drying to obtain the high-purity target compound. The method is simple and rapid in process synthesis, short in production period, low in production cost, high in target product total yield and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of photoresist additive synthesis technology, specifically relating to a method for synthesizing and purifying a trihydroxyphenol compound. Background Technology

[0002] Aromatic polyphenol monomers are important additives in photoresists, and their research helps improve the resolution, photosensitivity, and thermal stability of photoresists. In-depth research on these monomers may lead to the discovery of new, lower-cost synthesis methods, thereby reducing the production cost of photoresists. Simultaneously, new monomer structures may also lead to increased production efficiency, further promoting the development of the photoresist industry. On the other hand, aromatic polyphenol compounds contain multiple phenolic hydroxyl groups, and structurally similar analogs or isomers exist among polyphenolic hydroxyl compounds, increasing the difficulty of separation.

[0003] Trihydroxyphenols and their derivatives are important intermediates in the pharmaceutical and chemical industries, and their high-purity preparation process directly affects the performance of downstream products. Currently, solvent crystallization is commonly used for purification in industry; however, traditional processes suffer from technical bottlenecks such as uncontrollable product morphology and low separation efficiency due to insufficient control over crystallization kinetics and solvent interface effects. Specific limitations are manifested in the following aspects:

[0004] 1. The formation and separation of viscous substances are difficult in traditional processes.

[0005] In existing technologies, the polyhydroxy structure of trihydroxyphenolic compounds easily forms high-viscosity colloidal mixtures through intermolecular hydrogen bonds, accompanied by the generation of by-products, resulting in low separation efficiency and difficulty in industrialization. Plant polyphenols, such as extracts from lotus waste, have densely packed polar groups, making it difficult to obtain high-purity monomeric components that meet structural identification requirements even with multi-step purification methods such as silica gel column chromatography and gel chromatography [Chen Liang, Li Yiming, Chen Kaixian, et al. Research progress in the extraction and separation of plant polyphenolic components [J]. Chinese Herbal Medicines]. ,2013,44(11):7.DOI:10.7501 / j.issn.0253-2670.2013.11.027.][Pan Zhenhui, Wen Yuxin, Zheng Qingsong, et al. Research progress on extraction of active ingredients and their bioactivity from lotus waste[J]. Food Industry Technology,2021,42(15):8.DOI:10.13386 / j.issn1002-0306.2020070034.]. The separation of triterpenes from prickly pear requires normal-phase silica gel column chromatography coupled with reverse-phase preparative liquid chromatography, which is cumbersome and costly [Fu Yangyang, Liu Jiamin, Lu Xiaoluan, et al. Research progress on main active components and pharmacological effects of prickly pear [J]. Food Industry Technology, 2020, 41(13):9.DOI:10.13386 / j.issn1002-0306.2020.13.052.]. The application of macroporous resin in polyphenol purification also shows the dependence of high-purity natural product separation on composite processes [Wu Yonghua, Zhang Jianping, Zhao Jiechang, et al. Macroporous resin purification of Polygonatum polyphenols and its antioxidant properties and compositional analysis [J]. Transactions of the Chinese Society of Agricultural Engineering, 2020, 36(1):9.DOI:CNKI:SUN:NYGU.0.2020-01-038.].

[0006] 2. High solvent consumption and insufficient process economy

[0007] To improve the separation efficiency of viscous products, existing technologies often employ methods such as increasing solvent volume or multiple recrystallizations, but the solvent consumption problem during dissolution crystallization is prominent. Tan Junrui (Tan Junrui, Li Hui. Current Status and Development of Solution Crystallization Methods and Technologies [J]. University Chemistry, 2021, 36(04): 110-121) et al. pointed out that traditional processes require a large amount of anti-solvent to improve crystal yield, but the energy consumption of solvent recovery is high. For example, the purification of terephthalic acid requires the use of a DMF-water system, resulting in significant solvent recovery costs. In the bisphenol S purification process, although phenol can be recovered as a solvent, its high melting point increases the difficulty of operation, and the phenol residue in the product requires additional treatment. (Song Liqin. Optimization of Bisphenol S Synthesis Process and Its Efficient Separation [D]. Shanghai University of Applied Technology, 2022) In addition, induced freeze crystallization, such as the propofol purification patent, can control impurities through seed crystals, but multiple crystallizations still increase solvent consumption. (Shandong Weigao Pharmaceutical Co., Ltd., A purification method for high-purity propofol. 202110766075.0 [P]. 2022-09-06)

[0008] 3. Low product purity and uncontrollable crystal form

[0009] The polyhydroxy structure of trihydroxyphenol compounds readily forms a competitive hydrogen bond network with water molecules, leading to the formation of solvated crystals or mixed crystals. For example, Kitamura et al. (Kitamura, Mitsutaka. Thermodynamic stability and transformation of pharmaceutical polymorphs[J]. Pure & Applied Chemistry, 2005, 77(3):581-591.DOI:10.1351 / pac200577030581) demonstrated through antisolvent crystallization experiments that the rate of water addition significantly affects the stability of the crystal form. Low-rate addition (e.g., 0.28 ml / min) produces a thermodynamically stable α-crystal form, while high-rate addition (e.g., 1.42 ml / min) produces a mixture of metastable β-crystal form and amorphous phase, with significant fluctuations in product purity (85%-92%).

[0010] Improving the purification efficiency of trihydroxy compounds has been a major focus, with improvements primarily concentrated on the research, development, and refinement of equipment and additives, such as ultrasound-assisted crystallization, high-pressure crystallization, the use of amphiphilic additives, and supercritical fluid extraction. However, these methods still face challenges in practical applications. Ultrasound-assisted crystallization can accelerate nucleation, but cavitation corrosion in high-viscosity systems and low industrial energy efficiency limit its application. Supercritical fluid extraction (such as CO2) requires high-pressure equipment (10-40 MPa), is inefficient for polar compounds, and is costly. While amphiphilic additives (such as PEG) can improve crystal morphology, residues may lead to decreased stability. Furthermore, phenolic compounds are easily degraded under high temperatures and light, necessitating the development of more stable and low-cost targeted purification processes.

[0011] A comprehensive analysis of literature and patents indicates that one of the core problems in existing trihydroxy compound purification processes is the coexistence of polymorphs, which increases the difficulty of controlling the final product morphology, leading to low purification efficiency and insufficient purity. Conformational polymorphism differences cause lattice defects that adsorb impurities (e.g., the purity of dolutegravir intermediate is ≤98.44%), with isomer residues >1.0% and significant batch-to-batch fluctuations. By controlling the crystal form (e.g., co-crystallization or solvent screening), polymorphism can be suppressed, increasing purity to ≥99.50% and isomer impurities to ≤0.50% (Shanghai Disano Chemical Pharmaceutical Co., Ltd., A purification method for dolutegravir intermediate [P]. 202210731956.3, 2024-01-02). High-throughput crystallization screening further accelerates industrialization. Another core problem is the interference of phenolic hydroxyl-water molecule hydrogen bonding on crystallization behavior. Water molecules embed themselves in the lattice through OH…O hydrogen bonds, weakening the intermolecular forces and reducing lattice stability and packing density. Non-aqueous solvents or co-forming agents can partially reduce water interference, but there is still a lack of universal methods for regulating the multiple hydrogen bond networks of hydroxyl compounds. Summary of the Invention

[0012] Purpose of the invention: This invention solves the problems of low separation efficiency and insufficient purity caused by product adhesiveness in traditional processes, and provides a method for the synthesis and purification of trihydroxyphenol compounds that is simple, fast, has a short production cycle, low production cost, and high total yield of the target product.

[0013] Technical Solution: To solve the above-mentioned technical problems, the present invention provides a method for the synthesis and purification of trihydroxyphenol compounds, comprising the following steps:

[0014] (1) Dissolve crude resorcinol or its derivatives in methanol to obtain a solution, add methanol solutions of p-toluenesulfonic acid and ketone compounds dropwise to the solution, and carry out a catalytic reaction at 50-70°C to obtain a reaction solution;

[0015] (2) The reaction solution obtained in step (1) is added dropwise to deionized water at 0-5℃ at a rate of 1-3 mL / min, and a white solid is precipitated by stirring. The crude product is obtained by filtration.

[0016] (3) Dissolve the crude product in ethyl acetate, add silica gel powder for column chromatography, stir to adsorb, separate the supernatant and concentrate;

[0017] (4) Dissolve the concentrated solution in a mixed solvent of methanol and water, heat it to 60-65℃ to dissolve, and then cool it down to 5℃ or below at a rate of less than or equal to 0.5℃ / min. After crystallization, filter and dry to obtain the high-purity target compound.

[0018] In step (1), the amount of methanol used is 8 to 12 times the crude mass of resorcinol or its derivatives, and the amount of ketone compound is 1.0 to 1.5 times the molar mass of resorcinol.

[0019] The ketone compound mentioned in step (1) is one or more of cyclohexanone, acetone, 2-butanone or cyclopentanone.

[0020] In step (2), the temperature of the deionized water is 0 to 2°C, and the volume ratio of the reaction solution to the deionized water is 1:2 to 1:4.

[0021] In step (2), the stirring rate is 200-500 rpm and the precipitation time is 20-40 minutes.

[0022] In step (3), the amount of ethyl acetate used is 5 to 10 times the crude mass, and the stirring and adsorption time is 20 to 40 minutes.

[0023] In step (3), the silica gel powder for column chromatography has a mesh size of 200-300 and is added in an amount that is 1.5-2.5 times the crude product weight.

[0024] In step (4), the volume ratio of methanol to water is 1:3 to 5, and the gradient cooling rate is 0.3 to 0.5 °C / min.

[0025] In step (4), the total amount of mixed solvent used is 3 to 5 times the volume of concentrated liquid, and the crystallization settling time is 2 to 4 hours.

[0026] The mechanism of this invention is as follows: First, a catalytic reaction is initiated, in which resorcinol or its derivatives are dissolved in methanol, and a ketone compound (such as cyclohexanone, acetone, or 2-butanone) and a catalytic amount of p-toluenesulfonic acid are added, followed by stirring. Then, reverse low-temperature crystallization is performed, in which the reaction solution is added counter-currently to pre-cooled deionized water, precipitating a white solid under stirring. By controlling the low-temperature environment and the reverse addition sequence, an instantaneous high supersaturation is triggered, causing the solute molecules to undergo homogeneous nucleation, resulting in the precipitation of a loose crystalline crude product, shortening the crystallization time to 20–40 minutes. Next, purification is achieved through silica gel adsorption, in which the crude product is dissolved in ethyl acetate, and 200–300 mesh silica gel powder is added, followed by stirring and adsorption. After standing and separation, the clear liquid is separated and concentrated to 1 / 3–1 / 2 of its original volume. This step utilizes silica gel to selectively adsorb polar impurities and carbonization byproducts, avoiding interference from impurities during subsequent recrystallization. Next, the concentrate was dissolved in a mixture of methanol and water and recrystallized using a mixed solvent gradient. After complete dissolution by heating, the solution was cooled and allowed to stand to crystallize. By optimizing the solvent ratio and cooling rate, the solubility difference between the target substance and impurities was maximized. Finally, through solvent recovery and recycling, the methanol after crystallization was dehydrated and recovered using molecular sieves, and the aqueous phase was recycled for the crystallization process after reverse osmosis treatment. The total solvent consumption was reduced to ≤35L / kg of product.

[0027] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0028] (1) This invention overcomes the technical challenges of product gelation and low separation efficiency in the purification of trihydroxyphenol compounds by synergistically controlling crystallization kinetics through reverse dropping and low temperature. Compared with traditional processes, this invention enables the crude product to precipitate rapidly as a solid powder, reducing the filtration time from 3-4 hours in traditional processes to less than 30 minutes, increasing the solid-liquid separation efficiency by more than 80%, reducing solvent consumption by 40%, and ensuring stable product purity.

[0029] With a purity of ≥98% and a single crystal form, this process requires no complex equipment or additives, combining high efficiency and economy, and provides an innovative solution for the large-scale production of high-purity polyhydroxy compounds in the pharmaceutical and materials fields.

[0030] (2) This invention creatively optimizes the purification process of the target product and proposes a two-step purification linkage process for the crude target product. The first step uses silica gel to adsorb the unreacted raw materials in the crude product to achieve preliminary purification. The second step changes the conventional practice of recrystallization with a single solvent, which has a low yield and is difficult to obtain high purity. Instead, it uses a mixed solvent for recrystallization purification. This step can be completed in no more than 2 times to obtain the target product with a purity of over 98%.

[0031] (3) The solvent consumption in the purification process of the product of the present invention is significantly reduced, the amount of antisolvent (water) is reduced, multiple recrystallizations are not required, and the total solvent consumption is ≤350ml / 10g product, thus improving the economic efficiency of the process.

[0032] (4) The purification process of the product of the present invention does not require ultrasonic or high pressure equipment or additives, and the operating conditions are mild (0-10℃). It is suitable for the large-scale production of a variety of trihydroxyphenol compounds. The process is simplified and widely applicable, and does not use highly dangerous solvents, so it is safe. Attached Figure Description

[0033] Figure 1 This is a synthetic route diagram for the target compound of the present invention; where n is an integer ≤ 2, and R is: R-,-NO2.

[0034] Figure 2 LC-MS mass spectrum of the target product. Detailed Implementation

[0035] Example 1

[0036] A process for synthesizing and purifying a condensate of resorcinol and cyclohexanone, specifically including the following steps:

[0037] Step 1: Synthesis of the target product. Crude resorcinol (10.0 g, purity 85%) was dissolved in methanol (100 mL, analytical grade). The temperature was raised to 60 °C and stirred until completely dissolved. A methanol mixture of p-toluenesulfonic acid (0.2 g) and cyclohexanone (5.0 g) (10 mL) was added dropwise to the reaction solution. The reaction was maintained at 60 °C for 4 hours, and the reaction was detected by TLC plate.

[0038] Step 2: Reverse low-temperature crystallization. The reaction solution is added dropwise at a rate of 2 mL / min to 200 mL of deionized water pre-cooled to 2 °C. The stirring speed is 300 rpm, and a large amount of crystalline white solid precipitates out.

[0039] Step 3: Primary purification. The obtained white solid was filtered and dried under vacuum (50℃, 4h) without centrifugation to obtain the crude product. The crude product was dissolved in ethyl acetate (50mL), and silica gel powder (20g, 200-300 mesh) for column chromatography was added. The mixture was stirred for 30 minutes, allowed to stand for separation, and the clear liquid was separated.

[0040] Step 4: Recrystallization with mixed solvent: Concentrate the supernatant to 1 / 3 of its original volume, add a methanol-water mixed solvent (volume ratio 1:4), heat to 60℃ to dissolve, then cool to 5℃ in a gradient of 0.5℃ / min, filter and dry to obtain the target compound. NMR data of the target compound ( 1¹H NMR (400MHz, internal standard TMS, solvent DMSO-d6) is as follows: δppm 9.38 (s, 1H), 9.13 (s, 1H), 9.00 (s, 1H), 6.93 (d, J = 8.4Hz, 1H), 6.73 (d, J = 8.4Hz, 1H), 6.29–6.22 (m, 3H), 5.98 (dd, J = 1.6Hz, 8.4Hz, 1H), 3.18 (s, 1H), 1.72–1.50 (m, 18H). Mass spectrometry data are as follows: Positive ion mode: Theoretical value [M+H]+ = 381.21, Measured value [M+H]+ + =381.2; Negative ion mode: Theoretical value [MH] - =379.19, measured value [M+H] - =379.2.

[0041] (See Figure 2 LC-MS spectrum

[0042] Key parameters and data: The crude product precipitates as a white powdery solid, requiring no centrifugation, taking 30 minutes, with a yield of 88%, a melting point of 275–277℃ (capillary method, theoretical value 277℃), and a solubility of 0.3 mg / mL (water at 25℃, 75% lower than the crude product). The solvent consumption is 100 mL methanol + 200 mL water + 50 mL ethyl acetate = 350 mL / 10 g product, a 30% reduction compared to traditional processes. By counter-dropleting and low temperature (0–5℃) synergistically triggering instantaneous supersaturation (calculated value S = 1.8), combined with recrystallization using a methanol-water gradient ratio (1:4), selective suppression of impurity co-precipitation (solubility difference ΔS = 0.7 mg / mL) is achieved, transforming the product morphology from a viscous state to a crystalline powder (angle of repose optimized from >50° to 28°).

[0043] Example 2

[0044] A process for synthesizing and purifying a condensate of resorcinol and cyclohexanone, specifically including the following steps:

[0045] Step 1: The synthesis process of the target product is the same as Step 1 in Example 1.

[0046] Step 2: Reverse low-temperature crystallization. The reaction solution is added dropwise at a rate of 2 mL / min to 200 mL of deionized water pre-cooled to 2 °C. The stirring speed is 200 rpm. After stirring, a large amount of crystalline white solid precipitates out. The precipitation process takes 20 minutes.

[0047] Step 3: Primary purification. The obtained white solid was filtered and dried under vacuum (50℃, 4h) for 10 minutes without centrifugation to obtain crude product (8.8g). The crude product was dissolved in ethyl acetate (44mL), and silica gel powder (13.2g, 200 mesh, 1.5 times the mass of crude product) was added for column chromatography. The mixture was stirred for 20 minutes, allowed to stand for separation, and the clear liquid was separated.

[0048] Step 4: Recrystallize using a mixed solvent. Concentrate the supernatant to 1 / 3 of its original volume (14.7 mL), add a methanol-water mixed solvent (total volume 44.1 mL, 3 times the volume of the concentrated solution, methanol:water volume ratio 1:3), heat to 60 °C to dissolve, then cool to 5 °C at a gradient cooling rate of 0.3 °C / min, let stand for 2 hours, filter and dry to obtain the target compound. The results are similar to those in Example 1.

[0049] Key parameters and data: The crude product precipitated as a white powdery solid, requiring no centrifugation, taking 20 minutes, with a yield of 86% (slightly lower than Example 1, as the low stirring rate may have reduced the solid precipitation efficiency). Melting point 274-276℃, solubility 0.32 mg / mL (water at 25℃, 72% lower than the crude product); impurity inhibition effect was slightly weaker, possibly due to incomplete adsorption of silica gel with a lower mesh size (200 mesh). Solvent consumption was 100 mL methanol + 200 mL water + 44 mL ethyl acetate = 344 mL / 10 g product, a 28% reduction compared to the traditional process; counter-current addition and low temperature (0-5℃) synergistically triggered instantaneous supersaturation (calculated value S = 1.7), but the low stirring rate (200 rpm) may have led to uneven crystallization. The product repose angle was optimized from >50° to 30° because the methanol-to-water ratio of 1:3 and the short settling time (2 hours) may have affected the integrity of crystallization.

[0050] Example 3

[0051] A process for synthesizing and purifying a condensate of resorcinol and cyclohexanone, specifically including the following steps:

[0052] Step 1: The synthesis process of the target product is the same as Step 1 in Example 1.

[0053] Step 2: Reverse low-temperature crystallization. The reaction solution is added dropwise at a rate of 2 mL / min to 200 mL of deionized water pre-cooled to 2 °C. The stirring speed is 500 rpm. After stirring, a large amount of crystalline white solid precipitates out. The precipitation process takes 40 minutes.

[0054] Step 3: Primary purification. The obtained white solid was filtered off, which took 10 minutes and did not require centrifugation. The white solid was then vacuum dried (50℃, 4h) to obtain the crude product (approximately 8.8g). The crude product was dissolved in ethyl acetate (88mL), and silica gel powder for column chromatography (22.0g, 300 mesh, 2.5 times the mass of the crude product) was added. The mixture was stirred for 40 minutes, allowed to stand for separation, and the clear liquid was separated.

[0055] Step 4: Recrystallization with a mixed solvent. The supernatant was concentrated to 1 / 3 of its original volume (approximately 29.3 mL). A methanol-water mixed solvent (total volume 146.5 mL, 5 times the volume of the concentrated solution, methanol:water volume ratio 1:5) was added. The solution was heated to 60°C to dissolve, then cooled to 5°C at a gradient cooling rate of 0.5°C / min. The solution was allowed to stand for 4 hours, filtered, and dried to obtain the target compound. The results were similar to those in Example 1.

[0056] Key parameters and data: The crude product precipitated as a white powdery solid, requiring no centrifugation, taking 40 minutes, with a yield of 89% (slightly higher than Example 1, due to the high stirring rate of 500 rpm promoting uniform crystallization). Melting point 276-278℃, solubility 0.28 mg / mL (water at 25℃, 78% lower than the crude product). High silica gel addition (2.5 times) and a fineness (300 mesh) effectively adsorbed impurities, improving purity. Solvent consumption was 100 mL methanol + 200 mL water + 88 mL ethyl acetate = 388 mL / 10g product, a 25% reduction compared to traditional processes. Reverse dropping and low temperature (0-5℃) synergistically triggered instantaneous supersaturation (calculated value S = 1.9), but the high solvent consumption increased costs. The product's angle of repose was optimized from >50° to 26° (better than Example 1), due to a methanol-to-water ratio of 1:5 and a long settling time (4 hours) improving crystal size.

[0057] Comparative Example 1

[0058] A process for synthesizing and purifying a condensate of resorcinol and cyclohexanone, specifically including the following steps:

[0059] Step 1: The synthesis process of the target product is the same as Step 1 in Example 1.

[0060] Step 2: Forward crystallization. Pre-cooled deionized water (2℃, 200mL) is added dropwise to the reaction solution at a rate of 2mL / min, and the stirring speed is 300rpm. A large amount of sticky white substance is generated.

[0061] Step 3: Primary purification: Filter to obtain a viscous substance, centrifuge for 2.5 hours, and vacuum dry (50℃, 4h) to obtain crude product.

[0062] Step 4: Recrystallization with a single solvent. Dissolve the crude product obtained by filtration in methanol (100 mL), heat until the crude product is completely dissolved, and allow it to cool naturally to crystallize.

[0063] Key parameters and data: The precipitated substance was a viscous substance, requiring centrifugation, which took 2.5 hours; the yield was 72%, 16% lower than in Example 1; the melting point was 268-273℃, the solubility was 1.0 mg / mL, and significant impurity residue was observed. Solvent consumption was 150 mL methanol + 280 mL water + 70 mL ethyl acetate = 500 mL / 10 g product. Forward addition resulted in insufficient local supersaturation (S = 0.9), leading to a low nucleation rate.

[0064] Comparative Example 2

[0065] A process for synthesizing and purifying a condensate of resorcinol and cyclohexanone, specifically including the following steps:

[0066] Step 1: The synthesis process of the target product is the same as Step 1 in Example 1.

[0067] Step 2: Reverse low-temperature crystallization, same as step 2 in Example 1.

[0068] Step 3: Primary purification, same as step 3 in Example 1.

[0069] Step 4: Synthesis process of the target product, using methanol-water (1:2) mixed solvent, the rest is the same as step 4 of Example 1.

[0070] Key parameters and data: The product morphology is a mixture of fine powder and flocculent matter (angle of repose 45°), with a yield of 80% (loss due to co-extrusion of impurities); melting point 270-274℃; solvent consumption is 100mL methanol + 170mL water + 50mL ethyl acetate = 320mL / 10g product. A low water ratio (1:2) weakens the solubility difference (ΔS = 0.3 → 0.1mg / mL), making it impossible to effectively separate the target analyte from impurities.

[0071] Comparative Example 3

[0072] A process for synthesizing and purifying a condensate of resorcinol and cyclohexanone, specifically including the following steps:

[0073] Step 1: The synthesis process of the target product is the same as Step 1 in Example 1.

[0074] Step 2: Reverse low-temperature crystallization, same as step 2 in the example.

[0075] Step 3: Primary purification. The white solid obtained by filtration takes 30 minutes and does not require centrifugation. The white solid is then vacuum dried (50℃, 4h) to obtain the crude product.

[0076] Step 4: Recrystallize with mixed solvent. Concentrate the clear liquid to 1 / 3 of its original volume, add methanol-water mixed solvent (volume ratio 1:4), heat to 60℃ to dissolve, then cool to 5℃ in a gradient of 0.5℃ / min, filter and dry to obtain the target compound.

[0077] Key parameters and data: Product morphology: Visually observed flocculent mixture; yield: 78%; solvent consumption: 100mL methanol + 220mL water + 30mL ethyl acetate = 350mL / 10g product. The lack of silica gel adsorption for impurity removal resulted in a decrease in purity.

[0078] As can be seen from Comparative Example 1 above, when using the forward dropwise addition mode (antisolvent → reaction solution), the solvent polarity gradient changes gradually, causing solute molecules to slowly aggregate at low supersaturation, forming a viscous amorphous morphology, with solid-liquid separation time as long as 2.5 hours. This invention, through reverse dropwise addition (reaction solution → low-temperature antisolvent), triggers a sudden change in solvent interfacial tension, causing a sharp increase in local supersaturation, enhancing the nucleation rate, and forcing the crystallization process to be dominated by homogeneous nucleation, transforming the precipitated morphology from a viscous state to a loose crystalline powder.

[0079] Data from Examples 1-3 show that reverse dropping shortens the precipitation time to 30 minutes (an 80% increase in efficiency), significantly improving filtration efficiency (comparative Example 1's filtration time accounted for 62% of the total process time, while Example 1's accounted for only 12%). This invention experimentally verifies that a methanol-water volume ratio of 1:4 is the critical ratio for selective impurity removal. At this ratio, the difference in solubility between the target analyte and impurities increases. The solubility in Example 1 is 0.3 mg / mL, in Example 2 it is 0.32 mg / mL, and in Example 3 it is 0.28 mg / mL. Compared to the solubility of 1.0 mg / mL in Comparative Example 1, this invention significantly improves solubility. Combined with gradient cooling (60℃→0.3~5℃, 0.5℃ / min), it suppresses impurity co-precipitation. Mechanistic analysis indicates that a high water ratio (80%) enhances solute desolvation, disrupting the impurity hydrogen bond network, while the target analyte preferentially precipitates due to its higher lattice energy. In Examples 1-3, the impurity removal rate was improved by 40% at this ratio (the melting point range was optimized from 268-273℃ in Comparative Example 1 to 275-277℃, narrowing the range to 2℃), and the yield remained stable at over 86% (compared to 72% in Comparative Example 1), demonstrating significant overall benefits. Furthermore, the total solvent usage in Example 1 was 350 mL / 10g of product (100 mL methanol + 200 mL water + 50 mL ethyl acetate), a 30% reduction compared to the process in Comparative Example 1 (500 mL / 10g). The key innovations lie in the optimized solvent ratio (1:4) to reduce the number of washing cycles, and the reverse droplet addition to reduce solvent encapsulation loss (Comparative Example 1 required an additional 5L of washing solvent due to adhesive formation); methanol recovery rate ≥90% (rotary evaporation + molecular sieve dehydration), and the aqueous phase is treated by reverse osmosis and reused in the crystallization process, which conforms to the principles of green chemistry (COD emissions reduced by 60%); gradient cooling (0.5℃ / min) saves 30% more energy than natural cooling, and low-temperature crystallization (5℃) suppresses side reactions and reduces post-processing steps (Comparative Example 1 required additional activated carbon treatment due to carbonized impurities generated by high temperature).

Claims

1. A method for synthesizing and purifying a trihydroxyphenol compound, characterized in that, Includes the following steps: (1) Dissolve crude resorcinol or its derivatives in methanol to obtain a solution, add methanol solutions of p-toluenesulfonic acid and ketone compounds dropwise to the solution, and carry out a catalytic reaction at 50~70℃ to obtain a reaction solution; (2) The reaction solution obtained in step (1) is added dropwise to deionized water at 0-5℃ at a rate of 1-3 mL / min, and a white solid is precipitated by stirring. The crude product is obtained by filtration. (3) Dissolve the crude product in ethyl acetate, add silica gel powder for column chromatography and stir to adsorb, separate the supernatant and concentrate; (4) Dissolve the concentrated solution in a mixed solvent of methanol and water, heat it to 60~65℃ to dissolve, and then cool it down to 5℃ or below at a rate of less than or equal to 0.5℃ / min. After crystallization, filter and dry to obtain the high-purity target compound.

2. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The amount of methanol used in step (1) is 8 to 12 times the crude mass of resorcinol or its derivatives, and the amount of ketone compound is 1.0 to 1.5 times the molar mass of resorcinol.

3. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The ketone compound mentioned in step (1) is one or more of cyclohexanone, acetone, 2-butanone or cyclopentanone.

4. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The temperature of the deionized water in step (2) is 0~2℃, and the volume ratio of the reaction solution to the deionized water is 1:2~1:

4.

5. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The stirring speed in step (2) is 200~500 rpm, and the precipitation time is 20~40 minutes.

6. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The amount of ethyl acetate used in step (3) is 5 to 10 times the crude mass, and the stirring and adsorption time is 20 to 40 minutes.

7. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The silica gel powder used in step (3) has a mesh size of 200-300 and is added in an amount that is 1.5-2.5 times the crude product weight.

8. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The volume ratio of methanol to water in step (4) is 1:3~5, and the gradient cooling rate is 0.3~0.5℃ / min.

9. The method for synthesizing and purifying the trihydroxyphenol compound according to claim 1, characterized in that, The total amount of mixed solvent used in step (4) is 3 to 5 times the volume of the concentrated liquid, and the crystallization settling time is 2 to 4 hours.

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