A method for refining a sodium picosulfate intermediate

Abstract

The present invention provides a method for refining a sodium picosulfate intermediate. Aiming at the problems that it is difficult to remove the isomeric impurity I in the crude product of 4,4'-(2-pyridylmethylene)-bisphenol intermediate and the yield is relatively low, during the refining process, when the intermediate and the isomeric impurity I react with a specific salifying agent to form a salt, the resulting salt products have different solubilities in an alcohol solvent, and the dosage of the salifying agent and the temperature of the salt-forming reaction are controlled. The resulting salt product is precipitated under alkaline conditions, and high-purity 4,4'-(2-pyridylmethylene)-bisphenol can be obtained. The total yield reaches more than 75%, the purity reaches 99%, and the isomeric impurity I is less than 0.5%, realizing the effective separation of the intermediate and the impurity I.

Description

Technical Field

[0001] The present invention belongs to the technical field of raw drug preparation, and particularly relates to a refining method for a picosulfate sodium intermediate. Background Art

[0002] Sodium Picosulfate is a commonly used laxative in clinical practice with a unique mode of action. After being metabolized by enzymes produced by colonic flora, the drug generates active ingredients of diphenolic substances, which can directly act on the large intestine mucosa, promote intestinal peristalsis and inhibit water absorption in the intestine, showing a laxative effect.

[0003] Sodium Picosulfate has a mild laxative effect and is applicable to various constipation, postoperative adjuvant defecation, promoting excretion after contrast agent administration, excluding intestinal contents before surgery, pretreatment before large intestine examination (endoscopy), and excluding intestinal contents, etc.

[0004] The chemical name of Sodium Picosulfate is sodium 4,4'-(pyridine-2-ylmethylene)biphenyl disulfate monohydrate. This drug was first developed by DeAngeli Company in Italy and later introduced and developed by Teijin Pharma Limited in Japan, and obtained marketing approval under the trade name Laxoberon in May 1980.

[0005] Currently reported preparation methods for Sodium Picosulfate mainly include the following several:

[0006] Method 1 (Patent CN105175317A):

[0007]

[0008] Using 2-chlorophenol and 2-pyridinecarboxaldehyde as raw materials, carrying out a condensation reaction, reducing with nickel-aluminum alloy to obtain 4,4'-(2-pyridylmethylene)-biphenol, and then carrying out a sulfuric acid esterification reaction with chlorosulfonic acid, and adding sodium hydroxide for post-treatment to obtain Sodium Picosulfate. However, after the condensation of 2-chlorophenol and 2-pyridinecarboxaldehyde, it is inevitable to produce by-products of isomers of 4,4'-(2-pyridylmethylene)-biphenol, and it is difficult to remove them, resulting in a low purity of the final product; when nickel-aluminum alloy is used for dechlorination reduction, a large amount of hydrogen is released, which is not conducive to safe production.

[0009] Method 2 (Patents CN103086957A, CN113354574A):

[0010]

[0011] Using bisacodyl as the starting material, hydrolyzing with sodium hydroxide, and then using pyridine as the solvent for sulfonation esterification and salt formation to obtain Sodium Picosulfate. The starting materials of this method are not easily obtained, with a high price and high production costs.

[0012] Method 3 (Patent US2827465):

[0013]

[0014] Using 4,4'-dimethoxydiphenylacetonitrile and 2-bromopyridine as raw materials, a nucleophilic substitution reaction occurs to obtain 4,4'-dimethoxydiphenyl-(2-pyridyl)-acetonitrile. Refluxing with 48% hydrobromic acid causes the hydrolysis of the cyano group and the removal of the methyl group, resulting in 4,4'-dimethoxydiphenyl-(2-pyridyl)-acetamide. Then, heating under reflux in an aqueous potassium carbonate solution gives 4,4'-(2-pyridylmethylene)-bisphenol. Finally, a sulfuric acid esterification reaction is carried out with chlorosulfonic acid, and after adding sodium hydroxide for post-treatment, sodium picosulfate is obtained. This synthesis method has relatively complex operations, and the raw materials are not easily obtainable, making it unsuitable for industrial production.

[0015] Method 4 (Patents CN105294544B and CN105884678A):

[0016]

[0017] Phenol and 2-pyridinecarboxaldehyde are condensed, then a sulfuric acid esterification reaction is carried out on the phenolic hydroxyl group with chlorosulfonic acid, and finally sodium hydroxide is added to form a salt to obtain sodium picosulfate. In Patent CN105294544B, a heterogeneous reaction between phenol and pyridinecarboxaldehyde is carried out in a solvent-free environment. In a low-temperature reaction system, the reactants will be relatively viscous, making stirring inconvenient and having high requirements for production equipment. Although Patent CN105884678A uses chloroform as a solvent to solve the problem of uneven reaction, the subsequent purification process is relatively complex and the production cost is high.

[0018] When phenol and 2-pyridinecarboxaldehyde are condensed in Method 4, the yield of the product is relatively low, and the main impurity is the positional isomer impurity I: 4,2'-(2-pyridylmethylene)-bisphenol. Due to the similar nature of the isomers, it is difficult to refine.

[0019] For example, in Patent CN 113387877 A, phenol and 2-pyridinecarboxaldehyde are used as raw materials, and a condensation reaction is carried out under acidic conditions to prepare the intermediate 4,4'-(2-pyridylmethylene)-bisphenol. During the refinement of the intermediate, recrystallization is carried out using a mixture of methanol and ethyl acetate, and the content of the isomer impurity 4,2'-(2-pyridylmethylene)-bisphenol can be controlled below 0.5%. However, the yield of the intermediate is only 60 - 70%, with a low yield and being unsuitable for large-scale industrial production.

[0020] In Patent CN 112851574 A, concentrated sulfuric acid and 2-pyridinecarboxaldehyde were successively added dropwise to an acetonitrile solution of phenol for reaction. After the reaction was quenched, the pH was adjusted with a base, followed by neutralization and dispersion crystallization. The crude product was then refined with organic alcohol, but the yield was only about 50%, which is too low.

[0021] Therefore, it is particularly important to explore a refining method for the sodium picosulfate intermediate 4,4'-(2-pyridylmethylene)-bisphenol that is simple, has a high yield, and is easy to post-process. Summary of the Invention

[0022] Based on the existing technology, the object of the present invention is to provide a refining method for the sodium picosulfate intermediate 4,4'-(2-pyridylmethylene)-bisphenol to solve the problems that it is difficult to remove the isomeric impurity 4,2'-(2-pyridylmethylene)-bisphenol in the crude product of the sodium picosulfate intermediate 4,4'-(2-pyridylmethylene)-bisphenol and the yield is relatively low.

[0023] The technical solution of the present invention is as follows:

[0024] A refining method for a sodium picosulfate intermediate, which comprises the following steps:

[0025] (1) Preparation of the crude product: Using pyridine-2-carboxaldehyde and phenol as raw materials, a condensation reaction is carried out under the action of concentrated sulfuric acid. After the obtained reaction solution is quenched with water, the pH of the obtained mixed solution is adjusted to 8-9 at a temperature of 15-30 °C, filtered, and dried to obtain the crude product of the intermediate 4,4'-(2-pyridylmethylene)-bisphenol;

[0026] (2) Refining: Dissolve the crude product obtained in step (1) in an alcohol solvent, add a salifying agent and carry out a salification reaction at 15-35 °C. The obtained reaction solution is cooled to -10-10 °C, filtered, and the obtained salification product is washed and then dispersed in water. The pH of the mixed solution is adjusted to 8-9, filtered again, washed, and dried to obtain the refined product of 4,4'-(2-pyridylmethylene)-bisphenol;

[0027] Among them, in step (1), the crude product of 4,4'-(2-pyridylmethylene)-bisphenol contains impurity I, and its structural formula is as follows:

[0028]

[0029] For the present invention, the main impurity in the crude product of the intermediate 4,4'-(2-pyridylmethylene)-bisphenol is the isomeric impurity I. Since the impurity is an isomer of the target product and has a very similar structure, it is difficult to remove it by a simple recrystallization method, resulting in a relatively low yield of the target product 4,4'-(2-pyridylmethylene)-bisphenol. The key point of the refining method provided by the present invention is to remove impurity I.

[0030] The present invention aims at the problem that impurity I in the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol is difficult to remove. During the refining process of the obtained crude product, when the intermediate 4,4'-(2-pyridylmethylene)-bisphenol and isomeric impurity I react with a specific salifying agent to form salts, the resulting salt products have different solubilities in alcohol solvents. A method for removing impurity I is provided, and the dosage of the salifying agent and the temperature of the salt-forming reaction are controlled. After the salt-forming reaction, the obtained reaction solution is cooled and precipitated under alkaline conditions, and high-purity 4,4'-(2-pyridylmethylene)-bisphenol can be obtained, with a total yield of over 75%, a purity of 99%, and isomeric impurity I less than 0.5%, realizing the effective separation of the intermediate and impurity I.

[0031] In step (2), during the refining process of the crude product, the salifying agent selected in the present invention is p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid. During the salt-forming reaction, the resulting salt products have different solubilities in alcohol solvents, realizing the effective separation of the intermediate and impurity I. In a preferred embodiment, the salifying agent is p-toluenesulfonic acid.

[0032] For the present invention, during the refining process, the dosage of the salifying agent needs to be strictly controlled. If the dosage of the salifying agent is too low, impurity I in the crude product cannot be removed, resulting in poor refining effect; if the dosage of the salifying agent is too high, not only does impurity I react with the salifying agent to form salts, but also the intermediate reacts with the excessive salifying agent to form salts, resulting in a low yield and difficult to solve the problem of low yield commonly existing in the prior art, leading to poor refining effect.

[0033] In step (2), during the refining process, the mass ratio of the salifying agent to the crude product is 0.3 - 1.0:1, which can be but is not limited to 0.3:1, 0.4:1, 0.45:1, 0.5:1, 0.6:1, 0.65:1, 0.7:1, 0.74:1, 0.75:1, 0.8:1, 0.9:1 or 1.0:1. To achieve better results, the mass ratio of the salifying agent to the crude product is 0.45 - 0.8:1. Further preferably, the mass ratio of the salifying agent to the crude product is 0.65 - 0.74:1.

[0034] It should be noted that in step (2), after the salt-forming reaction, the obtained reaction solution is cooled and precipitated under alkaline conditions, and the pH of the mixed solution needs to be strictly controlled to 8 - 9. For example, the pH value is adjusted by adding sodium hydroxide. When the pH value is too large, the hydroxyl group in the salt product will form sodium salt with sodium hydroxide and dissolve in water, resulting in incomplete precipitation and affecting the yield; when the pH value is too small, the salt product will react with the salifying agent again to form secondary salts, and the resulting product is easily soluble in water and cannot be completely precipitated, affecting the yield.

[0035] In step (2), after the salt formation reaction, the obtained reaction solution is cooled, and the cooling temperature is -10 to 10 °C, which may be but is not limited to -10 to -5 °C, -10 to 0 °C, 0 to 5 °C or 0 to 10 °C. Preferably, the obtained reaction solution is cooled to 0 to 10 °C.

[0036] In step (2), during the refining process, the crude product obtained in step (1) is dissolved in an alcohol solvent, where the alcohol solvent is methanol, absolute ethanol or isopropanol. Preferably, the alcohol solvent is absolute ethanol.

[0037] In step (2), during the refining process, when the salt formation reaction is carried out, the reaction temperature is 15 to 35 °C, which may be but is not limited to 15 °C, 18 °C, 20 °C, 25 °C, 30 °C, 35 °C. To achieve better results, the temperature of the salt formation reaction is 20 to 30 °C.

[0038] Furthermore, the time of the salt formation reaction is 20 to 60 min, which may be but is not limited to 20 min, 30 min, 40 min, 50 min or 60 min. Preferably, the time of the salt formation reaction is 30 min.

[0039] In a preferred embodiment, the mass-volume ratio of the crude product to the alcohol solvent is 1:5 to 30 g / ml, which may be but is not limited to 1:5 g / ml, 1:8 g / ml, 1:10 g / ml, 1:12 g / ml, 1:15 g / ml, 1:18 g / ml, 1:20 g / ml, 1:25 g / ml or 1:30 g / ml. To achieve better results, the mass-volume ratio of the crude product to the alcohol solvent is 1:10 to 25 g / ml, and further preferably, the mass-volume ratio of the crude product to the alcohol solvent is 1:15 g / ml.

[0040] For the present invention, in step (1), when the condensation reaction is carried out, the reaction temperature is 10 to 30 °C, which may be but is not limited to 10 °C, 15 °C, 18 °C, 20 °C, 25 °C or 30 °C. To achieve better results, the temperature of the condensation reaction is 15 to 25 °C.

[0041] Furthermore, the time of the condensation reaction is 1 to 4 h, preferably, the time of the condensation reaction is 2 h.

[0042] In step (1), when the condensation reaction is carried out, the molar ratio of pyridine-2-carboxaldehyde to phenol is 1:1.5 to 3.5, which may be but is not limited to 1:1.5, 1:2.0, 1:2.3, 1:2.5, 1:2.7, 1:2.8, 1:3.0, 1:3.2 or 1:3.5. To achieve better results, the molar ratio of pyridine-2-carboxaldehyde to phenol is 1:2.5 to 3.0, and further preferably, the molar ratio of pyridine-2-carboxaldehyde to phenol is 1:2.7.

[0043] Adopting the technical solution of the present invention, the advantages are as follows:

[0044] Aiming at the problems that the isomeric impurity I in the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol is difficult to remove and the yield is relatively low, the present invention provides a refining method for the picosulfate sodium intermediate. During the refining process, when the intermediate 4,4'-(2-pyridylmethylene)-bisphenol and the impurity I form a salt with a specific salt-forming agent, the resulting salt-forming product has different solubilities in an alcohol solvent. By controlling the dosage of the salt-forming agent and the temperature of the salt-forming reaction, and precipitating the resulting salt-forming product under alkaline conditions, 4,4'-(2-pyridylmethylene)-bisphenol with high purity can be obtained. The total yield reaches more than 75%, the purity reaches 99%, and the isomeric impurity I is less than 0.5%, realizing the effective separation of the intermediate and the impurity I. Description of the Drawings

[0045] Figure 1 is the HPLC chromatogram of the crude product of the picosulfate sodium intermediate in Example 1 of the present invention;

[0046] Figure 2 is the HPLC chromatogram of the refined product of the picosulfate sodium intermediate in Example 1 of the present invention. Detailed Embodiments

[0047] The following examples further illustrate the refining method of the picosulfate sodium intermediate 4,4'-(2-pyridylmethylene)-bisphenol of the present invention, but these examples do not constitute any limitation to the present invention.

[0048] The data collection method of the present invention:

[0049] High performance liquid chromatography conditions: Using octadecylsilane bonded silica gel as the filler; Using phosphate buffer solution (taking 4.63 g of disodium hydrogen phosphate dodecahydrate and 0.2 g of cetyltrimethylammonium bromide, adding water to 1000 ml, and adjusting the pH to 7.5 with phosphoric acid) as mobile phase A, and acetonitrile as mobile phase B, with gradient elution as follows; The detection wavelength is 263 nm; The column temperature is 40 °C; The injection volume is 40 μl. The solvent for dissolving the sample to be measured is a mobile phase A-acetonitrile mixed solution (volume ratio 55:45).

[0050]

[0051] Example 1: Synthesis of intermediate 4,4'-(2-pyridylmethylene)-bisphenol

[0052] (1) Preparation of crude product: In a 1 L three-necked flask, add 47.4 g (0.504 mol) of phenol and 56 mL of acetonitrile. During stirring, cool the resulting mixed solution to 0 - 5 °C, and add 60.5 g of concentrated sulfuric acid dropwise. After adding, control the temperature at 5 - 15 °C and add dropwise a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After adding, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench, and control the temperature at 15 - 30 °C and add 20% sodium hydroxide solution dropwise to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 46.4 g (0.167 mol) of off-white solid, which is the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 89.3% and a purity of 94.55%, and the content of impurity I is 3.58%. The specific chromatogram is shown in Figure 1 。

[0053] (2) Refinement: Place 46 g of the crude product obtained in step (1) in a 1 L three-necked flask, add 690 mL of absolute ethanol, heat to complete dissolution, and then add 34 g of p-toluenesulfonic acid (w:w = 1:0.74). Under the condition of 20 - 30 °C, carry out the salt-forming reaction for 30 min during stirring. Cool the resulting reaction solution to 0 - 10 °C, filter, and wash. Disperse the obtained solid in 920 mL of water, stir until completely dissolved, adjust the pH of the mixed solution to 8 - 9 with 20% sodium hydroxide solution, filter, wash with water, and dry to obtain 41.5 g of white solid, which is the refined product of 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 90.2% and a purity of 99.45%, and the content of impurity I is 0.13%. The specific chromatogram is shown in Figure 2 。

[0054] Example 2: Synthesis of intermediate 4,4'-(2-pyridylmethylene)-bisphenol

[0055] (1) Preparation of crude product: In a 1 L three-necked flask, add 47.4 g (0.504 mol) of phenol and 56 mL of acetonitrile. During stirring, cool the resulting mixed solution to 0 - 5 °C, and add 60.5 g of concentrated sulfuric acid dropwise. After adding, control the temperature at 5 - 15 °C and add dropwise a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After adding, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench, and control the temperature at 15 - 30 °C and add 20% sodium hydroxide solution dropwise to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 46 g (0.166 mol) of off-white solid, which is the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 88.7% and a purity of 94.73%, and the content of impurity I is 3.49%.

[0056] (2) Purification: Place 46 g of the crude product obtained in step (1) into a 1 L three-necked flask, add 690 mL of absolute ethanol, heat until completely dissolved, then add 30 g of p-toluenesulfonic acid (w:w = 1:0.65). Under the condition of 20 - 30 °C, carry out the salt-forming reaction for 30 min during stirring. Cool the obtained reaction solution to 0 - 10 °C, filter, and wash. Disperse the obtained solid in 920 mL of water, stir until completely dissolved, adjust the pH of the mixed solution to 8 - 9 with 20% sodium hydroxide solution, filter, wash with water, and dry to obtain 40 g of white solid, which is the purified product of 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 86.9%, a purity of 99.44%, and the content of impurity I being 0.15%.

[0057] Example 3: Synthesis of Intermediate 4,4'-(2-Pyridylmethylene)-Bisphenol

[0058] (1) Preparation of the crude product: In a 1 L three-necked flask, add 35.1 g (0.373 mol) of phenol and 47 mL of acetonitrile. During stirring, cool the obtained mixed solution to 0 - 5 °C, and dropwise add 56.1 g of concentrated sulfuric acid. After dropping, control the temperature at 5 - 15 °C and dropwise add a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After dropping, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench, control the temperature at 15 - 30 °C, and dropwise add 20% sodium hydroxide solution to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 45.8 g (0.165 mol) of off-white solid, which is the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 88.3%, a purity of 93.8%, and the content of impurity I being 3.68%.

[0059] (2) Purification: Place 44 g of the crude product obtained in step (1) into a 1 L three-necked flask, add 440 mL of methanol, heat until completely dissolved, then add 30 g of benzenesulfonic acid (w:w = 1:0.68). Under the condition of 20 - 30 °C, carry out the salt-forming reaction for 30 min during stirring. Cool the obtained reaction solution to -10 - 0 °C, filter, and wash. Disperse the obtained solid in 880 mL of water, stir until completely dissolved, adjust the pH of the mixed solution to 8 - 9 with 20% sodium hydroxide solution, filter, wash with water, and dry to obtain 37.4 g of white solid, which is the purified product of 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 85%, a purity of 99.35%, and the content of impurity I being 0.21%.

[0060] Example 4: Synthesis of Intermediate 4,4'-(2-Pyridylmethylene)-Bisphenol

[0061] (1) Preparation of crude product: In a 1 L three-necked flask, add 52.7 g (0.560 mol) of phenol and 60 mL of acetonitrile. During stirring, cool the resulting mixed solution to 0 - 5 °C, and add 60.5 g of concentrated sulfuric acid dropwise. After adding, control the temperature at 5 - 15 °C and add dropwise a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After adding, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench it. Control the temperature at 15 - 30 °C and add 20% sodium hydroxide solution dropwise to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 45 g (0.162 mol) of off-white solid, which is the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 86.8% and a purity of 94.8%, and the content of impurity I is 3.26%.

[0062] (2) Refinement: Place 40 g of the crude product obtained in step (1) in a 1 L three-necked flask, add 1000 mL of isopropyl alcohol, heat until completely dissolved, and then add 18 g of methanesulfonic acid (w:w = 1:0.45). Under the condition of 20 - 30 °C, carry out the salt-forming reaction for 30 min during stirring. Cool the resulting reaction solution to -10 - 0 °C, filter, and wash. Disperse the obtained solid in 800 mL of water, stir until completely dissolved, adjust the pH of the mixed solution to 8 - 9 with 20% sodium hydroxide solution, filter, wash with water, and dry to obtain 34 g of white solid, which is the refined product of 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 85% and a purity of 99.31%, and the content of impurity I is 0.25%.

[0063] Comparative Example 1 Synthesis of Intermediate 4,4'-(2-pyridylmethylene)-bisphenol

[0064] (1) Preparation of crude product: In a 1 L three-necked flask, add 47.4 g (0.504 mol) of phenol and 56 mL of acetonitrile. During stirring, cool the resulting mixed solution to 0 - 5 °C, and add 60.5 g of concentrated sulfuric acid dropwise. After adding, control the temperature at 5 - 15 °C and add dropwise a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After adding, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench it. Control the temperature at 15 - 30 °C and add 20% sodium hydroxide solution dropwise to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 45.7 g (0.165 mol) of off-white solid, which is the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 88.1% and a purity of 93.9%, and the content of impurity I is 3.80%.

[0065] (2) Purification: Place 43 g of the crude product obtained in step (1) into a 1 L three-necked flask, add 660 mL of absolute ethanol, heat until completely dissolved, cool the resulting mixed solution to 0 - 10 °C, filter, and dry to obtain 28 g of a white solid, which is the purified product of 4,4'-(2-pyridylmethylene)-bisphenol. The yield is 65.1%, the purity is 98.3%, and the content of impurity I is 0.75%.

[0066] Comparative Example 2: Synthesis of Intermediate 4,4'-(2-pyridylmethylene)-bisphenol

[0067] (1) Preparation of the crude product: In a 1 L three-necked flask, add 47.4 g (0.504 mol) of phenol and 56 mL of acetonitrile. During stirring, cool the resulting mixed solution to 0 - 5 °C, and dropwise add 60.5 g of concentrated sulfuric acid. After dropping, control the temperature at 5 - 15 °C and dropwise add a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After dropping, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench, control the temperature at 15 - 30 °C, and dropwise add 20% sodium hydroxide solution to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 45.9 g (0.166 mol) of an off-white solid, which is the crude product of intermediate 4,4'-(2-pyridylmethylene)-bisphenol. The yield is 88.5%, the purity is 94.6%, and the content of impurity I is 3.21%.

[0068] (2) Purification: Place 41 g of the crude product obtained in step (1) into a 1 L three-necked flask, add 615 mL of absolute ethanol, heat until completely dissolved, then add 49 g of p-toluenesulfonic acid (w:w = 1:1.2). At 20 - 30 °C, carry out a salt-forming reaction for 30 min during stirring. Cool the resulting reaction solution to 0 - 10 °C, filter, and wash. Disperse the obtained solid in 820 mL of water, stir until completely dissolved, adjust the pH of the mixed solution to 8 - 9 with 20% sodium hydroxide solution, filter, wash with water, and dry to obtain 30 g of a white solid, which is the purified product of 4,4'-(2-pyridylmethylene)-bisphenol. The yield is 73.2%, the purity is 97.63%, and the content of impurity I is 1.22%.

[0069] Comparative Example 3: Synthesis of Intermediate 4,4'-(2-pyridylmethylene)-bisphenol

[0070] (1) Preparation of crude product: In a 1 L three-necked flask, add 47.4 g (0.504 mol) of phenol and 56 mL of acetonitrile. During stirring, cool the resulting mixed solution to 0 - 5 °C, and add 60.5 g of concentrated sulfuric acid dropwise. After dropping, control the temperature at 5 - 15 °C and add dropwise a mixture composed of 20 mL of acetonitrile and 20.0 g (0.187 mol) of pyridine-2-carboxaldehyde. After dropping, stir and react at 15 - 25 °C for 2 h. After the reaction is completed, add 50 mL of water to quench it, control the temperature at 15 - 30 °C, and add 20% sodium hydroxide solution dropwise to adjust the pH of the mixed solution to 8 - 9. Wait for the solid to precipitate, filter, and dry to obtain 46 g (0.166 mol) of off-white solid, which is the crude product of 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 88.8% and a purity of 93.3%, and the content of impurity I is 3.52%.

[0071] (2) Refinement: Place 45 g of the crude product obtained in step (1) in a 1 L three-necked flask, add 675 mL of absolute ethanol, heat until completely dissolved, then add 33.5 g of p-toluenesulfonic acid (w:w = 1:0.74). At 20 - 30 °C, carry out the salt-forming reaction for 30 min during stirring. Cool the resulting reaction solution to 0 - 10 °C, filter, and wash. Disperse the obtained solid in 900 mL of water, stir until completely dissolved, adjust the pH of the mixed solution to 10 - 11 with 20% sodium hydroxide solution, filter, wash with water, and dry to obtain 21 g of white solid, which is the refined product of 4,4'-(2-pyridylmethylene)-bisphenol, with a yield of 46.7% and a purity of 99.23%, and the content of impurity I is 0.42%.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: it is still possible to modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A refining method for a sodium picosulfate intermediate, characterized in that, it comprises the following steps: (1) Preparation of the crude product: Using pyridine-2-carboxaldehyde and phenol as raw materials, carrying out a condensation reaction under the action of concentrated sulfuric acid. After the obtained reaction solution is quenched with water, under the condition of a temperature of 15 - 30 °C, the pH of the obtained mixed solution is adjusted to 8 - 9, filtered, and dried to obtain the crude product of 4,4'-(2-pyridylmethylene)-bisphenol; (2) Refining: Dissolving the crude product obtained in step (1) in an alcohol solvent, adding a salifying agent to carry out a salification reaction at 15 - 35 °C. The obtained reaction solution is cooled to -10 - 10 °C, filtered. The obtained salification product is washed and then dispersed in water, the pH of the mixed solution is adjusted to 8 - 9, filtered again, washed, and dried to obtain the refined product of 4,4'-(2-pyridylmethylene)-bisphenol; wherein, in step (1), the crude product of 4,4'-(2-pyridylmethylene)-bisphenol contains impurity I, and its structural formula is as follows: In step (2), the mass ratio of the salifying agent to the crude product is 0.3 - 1.0:1; the salifying agent is p-toluenesulfonic acid, benzenesulfonic acid, or methanesulfonic acid; the alcohol solvent is methanol, absolute ethanol, or isopropanol.

2. The refining method for a sodium picosulfate intermediate according to claim 1, characterized in that, in step (2), the mass ratio of the salifying agent to the crude product is 0.45 - 0.8:

1.

3. The refining method for a sodium picosulfate intermediate according to claim 2, characterized in that, the mass ratio of the salifying agent to the crude product is 0.65 - 0.74:

1.

4. The refining method for a sodium picosulfate intermediate according to claim 3, characterized in that, in step (2), the salifying agent is p-toluenesulfonic acid.

5. The refining method for a sodium picosulfate intermediate according to claim 1, characterized in that, in step (2), the alcohol solvent is absolute ethanol.

6. The refining method for a sodium picosulfate intermediate according to claim 5, characterized in that, in step (2), the mass-to-volume ratio of the crude product to the alcohol solvent is 1:5 - 30 g / ml.

7. The refining method for a sodium picosulfate intermediate according to claim 6, characterized in that, in step (2), the mass-to-volume ratio of the crude product to the alcohol solvent is 1:10 - 25 g / ml.

8. The refining method for a sodium picosulfate intermediate according to claim 7, characterized in that, in step (2), the mass-to-volume ratio of the crude product to the alcohol solvent is 1:15 g / ml.

9. The refining method for a sodium picosulfate intermediate according to claim 1, characterized in that, in step (1), the condensation reaction temperature is 10 - 30 °C; the reaction time is 1 - 4 h.

10. The refining method for a sodium picosulfate intermediate according to claim 9, characterized in that, in step (1), the condensation reaction temperature is 15 - 25 °C; the reaction time is 2 h.

11. The refining method for a sodium picosulfate intermediate according to claim 1, characterized in that, in step (1), the molar ratio of pyridine-2-carboxaldehyde to phenol is 1:1.5 - 3.

5.

12. The purification method of the sodium picosulfate intermediate according to claim 1, characterized in that, in step (1), the molar ratio of pyridine-2-carboxaldehyde to phenol is 1:2.5 to 3.

0.

13. The purification method of the sodium picosulfate intermediate according to claim 1, characterized in that, in step (1), the molar ratio of pyridine-2-carboxaldehyde to phenol is 1:2.

7.

14. The purification method of the sodium picosulfate intermediate according to claim 1, characterized in that, in step (2), the temperature of the salt formation reaction is 20 to 30 °C; the reaction time is 20 to 60 min.

15. The purification method of the sodium picosulfate intermediate according to claim 14, characterized in that, in step (2), the temperature of the salt formation reaction is 20 to 30 °C; the reaction time is 30 min.

16. The purification method of the sodium picosulfate intermediate according to claim 1, characterized in that, in step (2), the obtained reaction solution is cooled to 0 to 10 °C and filtered.

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