A selective separation and purification method of 2,4-dihydroxybenzoic acid based on borate complexation-directional crystallization combination

Abstract

This invention discloses a selective separation and purification method for 2,4-dihydroxybenzoic acid based on a combination of boric acid complexation and directional crystallization, comprising the following steps: dissolving crude 2,4-dihydroxybenzoic acid containing isomers of 2,4-dihydroxybenzoic acid in a solvent; adding a phenylboronic acid derivative under stirring; adjusting the pH to 8.5–9.0; stirring and reacting at 45–70°C for 1–2 hours; filtering to obtain a first filtrate; concentrating the first filtrate by vacuum distillation; adjusting the pH of the concentrated solution to 2.0–3.0; performing programmed cooling crystallization from 50–78°C; filtering to obtain a second filter residue; and vacuum drying the second filter residue to obtain the product. The selective separation and purification method for 2,4-dihydroxybenzoic acid of this invention, through precise control of process parameters, can achieve a purity of 2,4-dihydroxybenzoic acid in the product exceeding 99.6%, a yield ≥86%, and an inorganic salt content <0.3%. Furthermore, it can form a closed-loop regeneration system to achieve efficient recovery and utilization of phenylboronic acid and the solvent.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical separation and purification technology, specifically relating to a selective separation and purification method for 2,4-dihydroxybenzoic acid based on the combined use of boric acid complexation and directional crystallization. Background Technology

[0002] 2,4-Dihydroxybenzoic acid (2,4-DHBA), also known as β-resorcinol, is a common organic synthesis reagent in laboratories and has important applications in pharmaceuticals, aerospace, and chemical analysis. The pharmaceutical and aerospace fields require high purity (>99%), but currently, no commercially available product meets these requirements. Synthetic methods for 2,4-dihydroxybenzoic acid include recrystallization, solvent extraction, and boric acid affinity chromatography. However, due to the similar physicochemical properties of dihydroxybenzoic acid isomers (e.g., 2,4-DHBA and 2,6-DHBA both have poor solubility), a single technique cannot achieve both selectivity and cost-effectiveness, and industrial scale-up is difficult. Traditional recrystallization has poor selectivity for isomers, with a purity limit of only 98%; the boric acid affinity chromatography alone can only remove the 1,2-dihydroxy isomer, also limiting the synthetic purity; combining solvent extraction with recrystallization or high-performance liquid chromatography can effectively improve product purity, but it consumes a large amount of organic solvents and is difficult to implement industrially. Therefore, none of these methods can simultaneously meet the demands of highly selective and economically efficient industrial production. Summary of the Invention

[0003] To address the shortcomings of existing technologies, the purpose of this invention is to provide a selective separation and purification method for 2,4-dihydroxybenzoic acid based on a combination of boric acid complexation and directional crystallization.

[0004] The objective of this invention is achieved through the following technical solutions.

[0005] A selective separation and purification method for 2,4-dihydroxybenzoic acid based on boric acid complexation-directional crystallization includes the following steps:

[0006] Step 1: Dissolve crude dihydroxybenzoic acid containing dihydroxybenzoic acid isomers in a solvent, add phenylboronic acid derivative under stirring, adjust the pH to 8.5-9.0, stir and react at 45-70℃ for 1-2 hours, filter to obtain the first filtrate, wherein the ratio of crude dihydroxybenzoic acid to phenylboronic acid derivative by mass is 100:(1-5);

[0007] In step 1, the phenylboronic acid derivative is one or more of 4-carboxyphenylboronic acid, 3-aminophenylboronic acid, potassium trifluoroborate, and β-alkoxyboronic acid.

[0008] In step 1, the solvent is an aqueous solution of an alcohol, and the alcohol is methanol or ethanol. The ratio of alcohol to water in the solvent by volume is (1-2):1.

[0009] In step 1, the ratio of the mass fraction of crude dihydroxybenzoic acid to the volume fraction of solvent is (1-3):5, where the mass fraction is in g and the volume fraction is in mL.

[0010] In step 1, the pH adjustment is achieved by using an aqueous sodium hydroxide solution with a concentration of 0.1–2.0 M.

[0011] Step 2: The first filtrate obtained in Step 1 is concentrated by vacuum distillation, and the pH of the concentrated solution is adjusted to 2.0-3.0. The solution is then subjected to programmed cooling crystallization from 50-78°C, filtered, and the second filter residue is obtained. The second filter residue is then dried under vacuum to obtain the product.

[0012] In step 2, the endpoint of vacuum distillation concentration is to concentrate to 30% to 50% of the original volume.

[0013] In step 2, the pH adjustment is achieved using hydrochloric acid, wherein the concentration of HCl in the hydrochloric acid is 0.1–2.0 M.

[0014] In step 2, the rate of programmed cooling crystallization is 0.1 to 2.0 °C / min. The programmed cooling crystallization process is carried out under vacuum until no more crystals continue to form.

[0015] In step 2, the temperature of vacuum drying is 45-65°C, and the vacuum degree of vacuum drying is maintained at 0.08-0.10 MPa.

[0016] In the above technical solution, the second filtrate obtained in step 2 is collected, and the pH of the second filtrate is adjusted to 1.0-1.5 to precipitate 2,6-dihydroxybenzoic acid. Compared with the prior art, the beneficial effects of the present invention are as follows:

[0017] 1. The selective separation and purification method for 2,4-dihydroxybenzoic acid of the present invention, by precisely controlling process parameters (such as temperature gradient, pH window, solvent ratio, etc.), can achieve a purity of 2,4-dihydroxybenzoic acid in the product of up to 99.6%, a yield of ≥86%, and an inorganic salt content of <0.3%. It can also form a closed-loop regeneration system to achieve efficient recovery and utilization of phenylboronic acid and solvent.

[0018] 2. In step 1, under pH conditions of 8.5–9.0, boric acid in the phenylboronic acid derivative is activated to B(OH)4. - B(OH)4 - It forms a five-membered ring complex (K) with 1,2-dihydroxybenzoic acid. b =103 M -1 That is, 1,2-dihydroxybenzoic acid specifically complexes with phenylboronic acid derivatives to form borate ester precipitates (the borate ester precipitates serve as the first filter residue), while 1,3-dihydroxybenzoic acid (including 2,4-dihydroxybenzoic acid and 2,6-dihydroxybenzoic acid) hardly reacts with B(OH)4. - reaction (K) b =10M -1 Boronate ester precipitates can be treated with hydrochloric acid to break the boronate ester bonds. After the boronate ester bonds are broken, they are separated by filtration. The filtrate can be concentrated to recover phenylboronic acid derivatives, with a recovery rate of ≥89%.

[0019] 3. In this invention, the vapor evaporated during vacuum distillation and the vapor evaporated during programmed cooling crystallization can be recovered by condensation to obtain solvent, with a solvent recovery rate of ≥88%.

[0020] 4. In step 2, filtration simultaneously yields a second filter residue and a second filtrate. The second filtrate can be used to separate 2,6-dihydroxybenzoic acid: In step 2, under pH conditions of 2.0–3.0, 2,4-dihydroxybenzoic acid in the solution precipitates due to supersaturation (saturation reaches 120%), while due to steric hindrance, the saturation of 2,6-dihydroxybenzoic acid is only 60% and remains in the solution (i.e., the intermediate product). By adjusting the pH of the obtained second filtrate to 1.0–1.5 with hydrochloric acid, 2,6-dihydroxybenzoic acid can be precipitated. Attached Figure Description

[0021] Figure 1 This is a flowchart of a selective separation and purification method for 2,4-dihydroxybenzoic acid based on a combination of boric acid complexation and directional crystallization.

[0022] Figure 2 The liquid chromatogram of crude dihydroxybenzoic acid is shown.

[0023] Figure 3 The following are liquid chromatograms of the products obtained in Examples 1-4. Detailed Implementation

[0024] The technical solution of the present invention will be further described in detail below with reference to the embodiments and accompanying drawings.

[0025] The crude dihydroxybenzoic acid containing dihydroxybenzoic acid isomers in the following examples was purchased from Jining Qicai Chemical Co., Ltd.

[0026] Example 1

[0027] A selective separation and purification method for 2,4-dihydroxybenzoic acid based on boric acid complexation-directional crystallization includes the following steps:

[0028] Step 1: In a reaction vessel, 100g of crude dihydroxybenzoic acid containing dihydroxybenzoic acid isomers is dissolved in a solvent to obtain solution A. 3-Aminophenylboronic acid is added to solution A under stirring to obtain solution B. Sodium hydroxide aqueous solution (0.1M concentration) is added to solution B to adjust the pH to 8.8. After stirring and reacting at 60℃ for 2 hours, the mixture is filtered while hot to obtain the first filtrate and the first filter residue. The solvent is an aqueous ethanol solution, with a volume ratio of ethanol to water of 1:1; the mass ratio of crude dihydroxybenzoic acid to 3-aminophenylboronic acid is 100:4.2; and the mass ratio of crude dihydroxybenzoic acid to solvent volume is 1:5. All mass parts are expressed in g, and volume parts are expressed in mL.

[0029] Step 2: Maintaining the reaction temperature at 60°C, concentrate the first filtrate obtained in Step 1 to 30% of its original volume by vacuum distillation to obtain solution D. Add hydrochloric acid (HCl concentration of 0.1M) to solution D to adjust the pH of solution D to 2.5. Perform programmed cooling crystallization of solution D from 60°C at a rate of 0.5°C / min under vacuum conditions until no more crystals continue to form, and stop to obtain an intermediate product. Filter the intermediate product to obtain a second filtrate and a second filter residue. Then, vacuum dry the obtained second filter residue at 60°C for 24 hours to finally obtain a white needle-like product. The vacuum degree of vacuum drying is maintained at 0.08-0.1 MPa.

[0030] The first filter residue obtained in step 1 is a borate ester precipitate formed by the specific complexation of 1,2-dihydroxybenzoic acid and 3-aminophenylboronic acid. The borate ester precipitate is soaked in hydrochloric acid (HCl concentration of 0.1M) and stirred at room temperature for 2 hours before filtration. The filtrate is concentrated to recover 3-aminophenylboronic acid.

[0031] Collect the second filtrate obtained from the filtration in step 2, and adjust the pH of the second filtrate to 1.0 with hydrochloric acid (HCl concentration in hydrochloric acid is 0.1M) to precipitate 2,6-dihydroxybenzoic acid.

[0032] Example 2

[0033] A selective separation and purification method for 2,4-dihydroxybenzoic acid based on boric acid complexation-directional crystallization includes the following steps:

[0034] Step 1: Dissolve 100g of crude dihydroxybenzoic acid containing dihydroxybenzoic acid isomers in a solvent to obtain solution A. Add 3-aminophenylboronic acid to solution A while stirring to obtain solution B. Add sodium hydroxide aqueous solution (0.1M concentration) dropwise to solution B to adjust the pH to 8.6. After stirring and reacting at 55℃ for 1.5h, filter while hot to obtain the first filtrate and the first filter residue. The solvent is an aqueous methanol solution, and the ratio of methanol to water in the solvent is 2:1 by volume. The ratio of crude dihydroxybenzoic acid to 3-aminophenylboronic acid is 100:3.8 by mass. The ratio of the mass fraction of crude dihydroxybenzoic acid to the volume fraction of the solvent is 1:6. The units of mass fraction are g and the units of volume fraction are mL.

[0035] Step 2: Maintaining the reaction temperature at 55℃, concentrate the first filtrate obtained in Step 1 to 30% of its original volume by vacuum distillation to obtain solution D. Add hydrochloric acid (HCl concentration of 0.1M) to solution D to adjust the pH of solution D to 2.8. Perform programmed cooling crystallization of solution D from 55℃ at a rate of 0.3℃ / min under vacuum conditions until no more crystals continue to form, and stop to obtain an intermediate product. Filter the intermediate product to obtain a second filtrate and a second filter residue. Then, vacuum dry the obtained second filter residue at 60℃ for 24 hours to finally obtain a white needle-like product. The vacuum degree of vacuum drying is maintained at 0.08-0.1MPa.

[0036] The first filter residue obtained in step 1 is a borate ester precipitate formed by the specific complexation of 1,2-dihydroxybenzoic acid and 3-aminophenylboronic acid. The borate ester precipitate is soaked in hydrochloric acid (HCl concentration of 0.1M) and stirred at room temperature for 2 hours before filtration. The filtrate is concentrated to recover 3-aminophenylboronic acid.

[0037] Collect the second filtrate obtained from the filtration in step 2, and adjust the pH of the second filtrate to 1.0 with hydrochloric acid (HCl concentration in hydrochloric acid is 0.1M) to precipitate 2,6-dihydroxybenzoic acid.

[0038] Example 3

[0039] A selective separation and purification method for 2,4-dihydroxybenzoic acid based on boric acid complexation-directional crystallization includes the following steps:

[0040] Step 1: Dissolve 100g of crude dihydroxybenzoic acid containing dihydroxybenzoic acid isomers in a solvent to obtain solution A. Add 4-carboxyphenylboronic acid to solution A while stirring to obtain solution B. Add sodium hydroxide aqueous solution (0.1M concentration) dropwise to solution B to adjust the pH to 9.0. After stirring and reacting at 55℃ for 1.5h, filter while hot to obtain the first filtrate and the first reddish-brown filter residue. The solvent is an aqueous ethanol solution, and the ratio of ethanol to water in the solvent is 1:1 by volume. The ratio of crude dihydroxybenzoic acid to 4-carboxyphenylboronic acid is 20:1 by mass. The ratio of the mass fraction of crude dihydroxybenzoic acid to the volume fraction of the solvent is 1:5. The units of mass fraction are g and the units of volume fraction are mL.

[0041] Step 2: Maintaining the reaction temperature at 55℃, concentrate the first filtrate obtained in Step 1 to 30% of its original volume by vacuum distillation to obtain solution D. Add hydrochloric acid (HCl concentration of 0.1M) to solution D to adjust the pH of solution D to 2.6. Perform programmed cooling crystallization of solution D from 60℃ at a rate of 0.5℃ / min under vacuum conditions until no more crystals continue to form, and stop to obtain an intermediate product. Filter the intermediate product to obtain a second filtrate and a second filter residue. Then, vacuum dry the obtained second filter residue at 60℃ for 24 hours to finally obtain a white prismatic product. The vacuum degree of vacuum drying is maintained at 0.08-0.1MPa.

[0042] The first filter residue obtained in step 1 is a borate ester precipitate formed by the specific complexation of 1,2-dihydroxybenzoic acid and 4-carboxyphenylboronic acid. The borate ester precipitate is soaked in hydrochloric acid (pH=1.8), stirred at room temperature for 2 hours, and then filtered. The filtrate is concentrated to recover 4-carboxyphenylboronic acid.

[0043] Collect the second filtrate obtained from the filtration in step 2, and adjust the pH of the second filtrate to 1.0 with hydrochloric acid (HCl concentration in hydrochloric acid is 0.1M) to precipitate 2,6-dihydroxybenzoic acid.

[0044] Example 4

[0045] A selective separation and purification method for 2,4-dihydroxybenzoic acid based on boric acid complexation-directional crystallization is basically the same as that in Example 1, except that:

[0046] Step 2: Maintaining the reaction temperature at 60°C, concentrate the first filtrate obtained in Step 1 to 30% of its original volume by vacuum distillation to obtain solution D. Transfer solution D to a crystallization vessel equipped with a Helmholtz coil magnetic field system. Add hydrochloric acid (HCl concentration of 0.1M) to solution D to adjust the pH to 2.5. Heat solution D to 60°C and start a 0.5T axial static magnetic field. Perform programmed cooling crystallization from 60°C at a rate of 0.5°C / min until no more crystals continue to form. Stop the process and turn off the magnetic field to obtain an intermediate product. Filter the intermediate product to obtain a second filtrate and a second filter residue. Then, vacuum dry the obtained second filter residue at 60°C for 24 hours to finally obtain a white needle-like product. The vacuum degree of vacuum drying is maintained at 0.08-0.1 MPa.

[0047] The first filter residue obtained in step 1 is a borate ester precipitate formed by the specific complexation of 1,2-dihydroxybenzoic acid and 3-aminophenylboronic acid. The borate ester precipitate is soaked in hydrochloric acid (HCl concentration of 0.1M) and stirred at room temperature for 2 hours before filtration. The filtrate is concentrated to recover 3-aminophenylboronic acid.

[0048] Collect the second filtrate obtained from the filtration in step 2, and adjust the pH of the second filtrate to 1.0 with hydrochloric acid (HCl concentration in hydrochloric acid is 0.1M) to precipitate 2,6-dihydroxybenzoic acid.

[0049] The purity of the products obtained by the selective separation and purification methods in Examples 1-4 was determined by titration. The specific determination method included: weighing 0.5000 g of the product into a 250 mL Erlenmeyer flask, dissolving it in 5 mL of ethanol, then adding 30 mL of distilled water and 5 drops of methyl red-methylene blue mixed indicator solution (purchased from Tianjin Fuchen Chemical Reagent Co., Ltd.). Titration was performed with 0.1 M sodium hydroxide aqueous solution (the concentration of sodium hydroxide in the sodium hydroxide aqueous solution was 0.1 M) until the solution turned bright green, at which point the titration was stopped. The purity of 2,4-dihydroxybenzoic acid in the product was calculated using the following formula:

[0050]

[0051] Where c is the molar concentration of sodium hydroxide in the sodium hydroxide aqueous solution (M), V is the volume of sodium hydroxide aqueous solution consumed (mL), 0.1541 is the molar mass of C7H6O4 (2,4-dihydroxybenzoic acid) (kg / mol), and m is the weighed mass of the product (g).

[0052] The purity (detected by HPLC) and yield of 2,4-dihydroxybenzoic acid in the products obtained by the selective separation and purification methods in Examples 1-4 are shown in Table 1.

[0053] Table 1

[0054] Group purity(%) Yield (%) Example 1 99.6％ 90％ Example 2 99.3％ 88％ Example 3 99.2％ 86％ Example 4 99.5％ 92％

[0055] The recovery rates of the solvent and phenylboronic acid derivatives recovered in the selective separation and purification methods of Examples 1-4 were calculated, and the results are shown in Table 2.

[0056] Table 2

[0057]

[0058]

[0059] The crude dihydroxybenzoic acid and the products obtained by the selective separation and purification methods of Examples 1-4 were analyzed by liquid chromatography. The specific testing method included: accurately weighing 0.0040 g of sample into a 25 mL volumetric flask, adding methanol-water solution to dissolve and dilute to 25 mL. After thorough mixing, the mixture was injected at a volume of 5 μL. The mobile phase was 0.2% phosphoric acid:methanol:acetonitrile = 50:40:10 (volume ratio). The detection wavelength was 230 nm, the flow rate of the mobile phase was 0.6 mL / min, and the acquisition time was 30 min. The sample was one of the crude dihydroxybenzoic acid and the products obtained by the selective separation and purification methods of Examples 1-4. The methanol-water solution had a methanol-to-water ratio of 1:1 (volume fraction). The 0.2% phosphoric acid in the mobile phase was a 0.2% phosphoric acid aqueous solution. The detection results are shown below. Figures 2-3 .

[0060] The results above show that the impurity peaks of the products obtained by the selective separation and purification methods in Examples 1 and 4 are smaller than those in Examples 2 and 3, and the purity of 2,4-dihydroxybenzoic acid in the products is higher. This is because the phenylboronic acid derivative used in Example 3 is 4-carboxyphenylboronic acid, which has greater steric hindrance of the carboxyl group, resulting in a slightly lower removal rate of 1,2-dihydroxybenzoic acid. In contrast, Examples 1 and 4 use 3-aminophenylboronic acid, where the amino group can synergistically enhance the removal of B(OH)4 with the boron atom. - The complexation ability with the ortho- and tho-dihydroxyl groups enables the efficient removal of 1,2-dihydroxybenzoic acid. In Example 2, the solvent used was an aqueous methanol solution. Compared to Example 1, the removal rate of isomers in the system was lower, and the methanol system was more toxic than the ethanol system. Compared to the conventional temperature-programmed crystallization method used in Example 1, the 0.5T axial static magnetic field-assisted crystallization used in Example 4 promoted molecular orientation, further improving the yield while ensuring crystal purity.

[0061] The inorganic salt content in the products obtained by the selective separation and purification methods in Examples 1-4 was detected according to the "General Method for Determination of Residue on Ignition of Chemical Reagents (GB / T 9741)". The results are shown in Table 3.

[0062] Table 3

[0063] Group Inorganic salt content (wt%) Example 1 0.24％ Example 2 0.21％ Example 3 0.25％ Example 4 0.19％

[0064] As shown in Table 3, the inorganic salt content of the products obtained by the selective separation and purification methods in Examples 1 to 4 is all <0.3%.

[0065] The present invention has been described above by way of example. It should be noted that any simple modifications, alterations or other equivalent substitutions that can be made by those skilled in the art without creative effort without departing from the core of the present invention fall within the protection scope of the present invention.

Claims

1. A selective separation and purification method for 2,4-dihydroxybenzoic acid based on boric acid complexation-directional crystallization, characterized in that, Includes the following steps: Step 1: Dissolve crude dihydroxybenzoic acid containing dihydroxybenzoic acid isomers in a solvent, add phenylboronic acid derivative under stirring, adjust the pH to 8.5-9.0, stir and react at 45-70℃ for 1-2 hours, filter to obtain the first filtrate, wherein the ratio of crude dihydroxybenzoic acid to phenylboronic acid derivative by mass is 100:(1-5); Step 2: The first filtrate obtained in Step 1 is concentrated by vacuum distillation, and the pH of the concentrated solution is adjusted to 2.0-3.

0. The solution is then subjected to programmed cooling crystallization from 50-78°C, filtered, and the second filter residue is obtained. The second filter residue is then dried under vacuum to obtain the product.

2. The selective separation and purification method according to claim 1, characterized in that, In step 1, the phenylboronic acid derivative is one or more of 4-carboxyphenylboronic acid, 3-aminophenylboronic acid, potassium trifluoroborate, and β-alkoxyboronic acid.

3. The selective separation and purification method according to claim 1, characterized in that, In step 1, the solvent is an aqueous solution of an alcohol, and the alcohol is methanol or ethanol. The ratio of alcohol to water in the solvent by volume is (1-2):

1.

4. The selective separation and purification method according to claim 1, characterized in that, In step 1, the ratio of the mass fraction of crude dihydroxybenzoic acid to the volume fraction of solvent is (1-3):5, where the mass fraction is in g and the volume fraction is in mL.

5. The selective separation and purification method according to claim 1, characterized in that, In step 1, the pH adjustment is achieved by using an aqueous sodium hydroxide solution with a concentration of 0.1–2.0 M.

6. The selective separation and purification method according to claim 1, characterized in that, In step 2, the endpoint of vacuum distillation concentration is to concentrate to 30% to 50% of the original volume.

7. The selective separation and purification method according to claim 1, characterized in that, In step 2, the pH adjustment is achieved using hydrochloric acid, wherein the concentration of HCl in the hydrochloric acid is 0.1–2.0 M.

8. The selective separation and purification method according to claim 1, characterized in that, In step 2, the rate of programmed cooling crystallization is 0.1 to 2.0 °C / min. The programmed cooling crystallization process is carried out under vacuum until no more crystals continue to form.

9. The selective separation and purification method according to claim 1, characterized in that, In step 2, the temperature of vacuum drying is 45-65°C, and the vacuum degree of vacuum drying is maintained at 0.08-0.10 MPa.

10. The selective separation and purification method according to claim 1, characterized in that, Collect the second filtrate obtained in step 2, adjust the pH of the second filtrate to 1.0-1.5, and precipitate 2,6-dihydroxybenzoic acid.

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