A process for the preparation of sodium picosulphate

Abstract

The application belongs to the technical field of biological medicine, and relates to synthesis of a medicine, in particular to a preparation method of picrosulfa sodium. Phenol and 2-pyridine formaldehyde are used as raw materials, trifluoroacetic acid and formic acid are used as reaction solvents, concentrated sulfuric acid is added dropwise, 4,4'-(2-pyridine methylene)-bisphenol crude product is obtained after the reaction is completed, the 4,4'-(2-pyridine methylene)-bisphenol crude product is refined to obtain 4,4'-(2-pyridine methylene)-bisphenol pure product; the 4,4'-(2-pyridine methylene)-bisphenol pure product is subjected to a sulfonation reaction by using sulfur trioxide pyridine complex, and then subjected to an alkali neutralization reaction to obtain picrosulfa sodium crude product, and the picrosulfa sodium crude product is refined to obtain picrosulfa sodium pure product. The application can reduce the generation of isomers, improve the yield, is suitable for industrial production, and the prepared picrosulfa sodium meets the requirements of the quality standard of the European Pharmacopoeia.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and relates to synthesis of a medicine, in particular to a preparation method of sodium picosulfate. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing an understanding of the general background of the application and does not necessarily constitute an admission or a recognition that the information forms part of the prior art that is already known in any jurisdiction.

[0003] Sodium picosulfate is a laxative. The earliest disclosed preparation method thereof is to use phenol as a raw material, to perform condensation reaction with 2-pyridine carboxylic acid under the action of sulfuric acid to obtain 4,4'-(2-pyridine methylene)-bisphenol, and then to perform sulfonation reaction with sulfur trioxide pyridine complex and neutralization with alkali to obtain sodium picosulfate. The reaction route is as follows:

[0004]

[0005] However, in the synthesis process of the above method, the system is viscous and not easy to stir, which is not suitable for industrial production. In addition, isomer impurities are inevitably produced, and the two have similar properties and are difficult to remove, which affects the quality of the final product sodium picosulfate. Although trichloromethane and acetonitrile are added as solvents to change the reaction into a homogeneous phase, the problem of by-products still exists. According to the research of the inventors, the addition of ethylene glycol can reduce the production of by-products, but it is necessary to add cuprous chloride and ferrous ammonium sulfate to further improve the purity through complexation. At this time, new metal ion impurities are introduced, increasing the risk of the product.

[0006] In addition, the inventors have found in research that the sodium picosulfate prepared by the existing method sometimes passes the clarity test and sometimes does not, and there is a problem of instability of the clarity test result. SUMMARY

[0007] In order to solve the problems of the prior art, the purpose of the present application is to provide a preparation method of sodium picosulfate, which can reduce the production of isomers, improve the yield, is suitable for industrial production, and the prepared sodium picosulfate meets the quality standard requirements of the European Pharmacopoeia.

[0008] In order to achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0009] A preparation method of sodium picosulfate, taking phenol and 2-pyridine formaldehyde as raw materials, trifluoroacetic acid and formic acid as reaction solvents, adding concentrated sulfuric acid dropwise under the condition of 0-5 DEG C, then heating to 30-50 DEG C to react, after the reaction is completed, obtaining 4, 4 '-(2-pyridine methylene)-bisphenol crude product, carrying out intermediate refining on the 4, 4 '-(2-pyridine methylene)-bisphenol crude product to obtain 4, 4 '-(2-pyridine methylene)-bisphenol pure product;

[0010] Sulfonating reaction is carried out on the 4, 4 '-(2-pyridine methylene)-bisphenol pure product by adopting sulfur trioxide pyridine complex, then alkali neutralization reaction is carried out to obtain sodium picosulfate crude product, product refining is carried out on the sodium picosulfate crude product to obtain sodium picosulfate pure product;

[0011] The process of intermediate refining is that: the mixture of alcohol organic matter and formate organic matter is used as refining solvent, the 4, 4 '-(2-pyridine methylene)-bisphenol crude product is added into the refining solvent and heated to dissolve, acid is added to adjust pH to 4.5-6.5, cooling and crystallization are carried out, and filtration is carried out.

[0012] The process of product refining is that: the sodium picosulfate crude product is added into ethanol aqueous solution and heated to dissolve, then activated carbon is added and stirred, then hot filtration is carried out, the filtrate of hot filtration is filtered through a PTFE filter membrane, the filtrate after filtering the filter membrane is heated to 65-75 DEG C, then cooling to 0-20 DEG C to crystallize, filtration and drying are carried out.

[0013] Through analyzing multiple batch experimental data results, it is found that the clarity of sodium picosulfate has a certain relationship with the content of isomer impurity 2, 4 '-(2-pyridine methylene)-bisphenol in intermediate 4, 4 '-(2-pyridine methylene)-bisphenol, when the content of 2, 4 '-(2-pyridine methylene)-bisphenol is >0.05%, the derived impurities generated in the subsequent preparation process of sodium picosulfate will affect the detection stability of the clarity of sodium picosulfate, when the content of 2, 4 '-(2-pyridine methylene)-bisphenol is <0.05%, the clarity is qualified after hot filtration PTFE membrane, multiple batches can be repeated, and the European Pharmacopoeia standard is met.

[0014]

[0015] The beneficial effects of the present application are:

[0016] (1) The present application makes the reaction into a homogeneous reaction system by using trifluoroacetic acid and formic acid as reaction solvents, reduces the generation of isomers, improves the yield, and is suitable for industrial production.

[0017] (2) The application discloses a method for refining an intermediate 4,4'-(2-pyridylmethylene)-bisphenol, which is purified through an acidic organic system with pH value being 4.5-6.5, can effectively remove isomer impurities contained in the intermediate, and finally the isomer impurity 2,4'-(2-pyridylmethylene)-bisphenol is controlled to be less than 0.05% through the process, so that the high-purity intermediate 4,4'-(2-pyridylmethylene)-bisphenol is obtained. It is found through experiments that the clarity of sodium picosulfate has a certain relationship with the derived impurity of the isomer impurity 2,4'-(2-pyridylmethylene)-bisphenol. When the isomer impurity 2,4'-(2-pyridylmethylene)-bisphenol is controlled to be less than 0.05%, the derived impurity in the product in multiple batches is not detected.

[0018] (3) The PTFE filter membrane is used in the refining process of the application, then the product API is obtained through crystallization by reducing temperature. The PTFE filter membrane can greatly improve the clarity of the refined solution, and further improve the clarity of the product.

[0019] (4) In the application, the intermediate is refined through the acidic organic system with pH value being 4.5-6.5, the isomer impurity is controlled, and then the PTFE filter membrane is used in the refining process of the sodium picosulfate (API) to improve the solution clarity. The two conditions are indispensable, and the combined action can solve the problem that the detection result of the clarity of the sodium picosulfate prepared through the existing process is unstable, and the product with qualified clarity according to the European Pharmacopoeia API can be stably obtained. BRIEF DESCRIPTION OF DRAWINGS

[0020] The drawings accompanying the specification of the application form a part of the application and serve to further understand the application. The schematic embodiments of the application and the description thereof are used to explain the application, and do not constitute an improper limitation on the application.

[0021] Figure 1 It is the HPLC spectrum of the 4,4'-(2-pyridylmethylene)-bisphenol crude product in the embodiment 1 of the application;

[0022] Figure 2 It is the HPLC spectrum of the 4,4'-(2-pyridylmethylene)-bisphenol after refining in the embodiment 1 of the application;

[0023] Figure 3 It is the HPLC spectrum of the sodium picosulfate in the embodiment 1 of the application;

[0024] Figure 4 It is the HPLC spectrum of the 4,4'-(2-pyridylmethylene)-bisphenol in the comparative example 1 of the application. DETAILED DESCRIPTION

[0025] It should be noted that the following detailed description is exemplary in nature and is intended to provide further description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0026] It is also important to note that the terms used herein are not intended to limit the particular embodiments of the present application disclosed in this specification. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an overly literal or overly formal sense unless expressly so defined herein.

[0027] In view of the problems of low purity and unstable clarity test results in the existing process for preparing sodium picosulfate, the present application provides a preparation method of sodium picosulfate.

[0028] In a typical embodiment of the present application, a preparation method of sodium picosulfate is provided, which uses phenol and 2-pyridine formaldehyde as raw materials, trifluoroacetic acid and formic acid as reaction solvents, drops concentrated sulfuric acid under the condition of 0-5℃, and then heats to 30-50℃ for reaction. After the reaction is completed, 4,4'-(2-pyridine methylene)-bisphenol crude product is obtained. The 4,4'-(2-pyridine methylene)-bisphenol crude product is refined to obtain 4,4'-(2-pyridine methylene)-bisphenol pure product.

[0029] The 4,4'-(2-pyridine methylene)-bisphenol pure product is subjected to sulfonation reaction by using sulfur trioxide pyridine complex, and then subjected to base neutralization reaction to obtain sodium picosulfate crude product. The sodium picosulfate crude product is refined to obtain sodium picosulfate pure product.

[0030] In the process of intermediate refining, a mixture of alcohol organic matter and formate organic matter is used as a refining solvent, the 4,4'-(2-pyridine methylene)-bisphenol crude product is added to the refining solvent for heating and dissolving, acid is added to adjust the pH to 4.5-6.5, and then cooling and crystallization and filtration are performed.

[0031] In the process of product refining, the sodium picosulfate crude product is added to an ethanol aqueous solution for heating and dissolving, activated carbon is added for stirring, and then hot filtration is performed. The filtrate of the hot filtration is filtered through a PTFE filter membrane, the filtrate after the filtration of the filter membrane is heated to 65-75℃, and then cooled to 0-20℃ for crystallization, filtration and drying.

[0032] In some embodiments, the molar ratio of 2-pyridine formaldehyde to phenol is 1:2.1-3.0, preferably 1:2.2-2.4.

[0033] In some embodiments, the ratio of trifluoroacetic acid to formic acid is 1:1-4, preferably 1:1.5-2.5.

[0034] In some embodiments, the ratio of the reaction solvent to 2-pyridinecarboxaldehyde is 1:1-5, preferably 1:1.5-2.5.

[0035] In some embodiments, the ratio of concentrated sulfuric acid to 2-pyridinecarboxaldehyde is 1:0.5-2, preferably 1:0.8-1.2.

[0036] In some embodiments, after adding concentrated sulfuric acid, the reaction is heated to 38-42°C.

[0037] In some embodiments, the reaction time for preparing 4,4'-(2-pyridinemethylene)- bisphenol is 2-8h.

[0038] In some embodiments, after the reaction of phenol and 2-pyridinecarboxaldehyde is complete, the temperature is lowered to 3-7°C, an aqueous ethanol solution is added, and the pH is adjusted to neutral with a base, and the mixture is stirred at 5-15°C, filtered, and the filter cake is washed with water to obtain 4,4'-(2-pyridinemethylene)-bisphenol crude product.

[0039] In some embodiments, the alcohol organic compound is ethanol, isopropanol, or n-propanol.

[0040] In some embodiments, the formate organic compound is isopropyl formate, butyl formate, ethyl formate, or methyl formate.

[0041] In some embodiments, the refining solvent is a mixture of ethanol and isopropyl formate.

[0042] In some embodiments, the acid used to adjust the pH is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid, and oxalic acid, preferably hydrochloric acid.

[0043] In some embodiments, during the intermediate refining process, the pH is adjusted to 5-6.

[0044] In some embodiments, the ratio of sulfur trioxide pyridine complex to 4,4'-(2-pyridinemethylene)-bisphenol crude product is 1:0.5-1.5, preferably 1:0.8-1.2.

[0045] In some embodiments, the temperature of the sulfonation reaction is 45-55°C, and the reaction time is 10-14h.

[0046] In some embodiments, the process of the base neutralization reaction is as follows: the material after the sulfonation reaction is cooled to 3-7°C, water and sodium hydroxide solution are added, and the pH is adjusted to 8-10.

[0047] In some embodiments, after the base neutralization reaction, dichloromethane is used for extraction, the extracted aqueous phase is concentrated under reduced pressure to obtain a solid, the solid is added to an ethanol aqueous solution, heated to reflux, hot filtered, the filtrate is cooled to precipitate crystals, filtered at 4-6°C to obtain a crude sodium picosulfate product.

[0048] In some embodiments, during the product refining process, the volume ratio of ethanol to water in the ethanol aqueous solution is 4-10:1, preferably 8-10:1.

[0049] In some embodiments, during the product refining process, the filtrate after membrane filtration is heated to 65-75°C and held for 0.5-2h.

[0050] In some embodiments, during the product refining process, the crystallization time is 1-3h.

[0051] In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples and comparative examples.

[0052] Example 1:

[0053] 1. Synthesis of 4,4'-(2-pyridylmethylene)-bisphenol

[0054] Preparation: In a reaction bottle, trifluoroacetic acid (7ml), formic acid (14ml) were stirred to form a mixed solution, then phenol (20.0g, 0.21mol), 2-pyridinecarboxaldehyde (10g, 0.09mol) were added, stirred to dissolve completely at room temperature, cooled to 0°C, added concentrated sulfuric acid (10g) dropwise, after the dropwise addition was completed, the temperature was raised to 40°C, and the reaction was stirred for 2h. The temperature was lowered to 5°C, 10ml water and 30ml ethanol were added, and the pH was adjusted to 7 with 30% sodium hydroxide solution, and the mixture was stirred at 5-15°C for 2h. The mixture was filtered, the filter cake was washed with water, and a crude 4,4'-(2-pyridylmethylene)-bisphenol was obtained, as shown in Figure 1 .

[0055] Refining: The crude 4,4'-(2-pyridylmethylene)-bisphenol was transferred into a single-neck flask, 50ml of an ethanol / formic acid isopropyl ester mixed solution (1:5) was added to dissolve the mixture, hydrochloric acid was added dropwise to adjust the pH to 5, and the mixture was stirred for 2h. The mixture was cooled to precipitate crystals, and the temperature was held at 5°C for 1h. The mixture was filtered, the filter cake was washed with a small amount of formic acid isopropyl ester, and a white solid was obtained by drying, with a yield of 17.8g, a purity of 99.8%, and an isomer impurity of 2,4'-(2-pyridylmethylene)-bisphenol of 0.03%, as shown in Figure 2 .

[0056] 2. Synthesis of sodium picosulfate

[0057] Preparation: In a reaction flask, add pyridine (50 ml), intermediate (10 g, 0.04 mol), sulfur trioxide pyridine complex (10 g, 0.06 mol), heat to 50 °C, and keep the temperature for 12 h. After the reaction is completed, cool to 5 °C, add 50 ml of water, adjust pH = 9 with 30% sodium hydroxide solution, extract with dichloromethane (50 ml x 2), and store the organic phase. The aqueous phase is concentrated under reduced pressure to obtain a solid. Add 70 ml of 90% ethanol / water solution, heat to reflux, hot filtration, cool the filtrate to precipitate, filter at 5 °C, and rinse the filter cake with a small amount of ethanol to obtain crude sodium picosulfate.

[0058] Refining: Take the crude sodium picosulfate, add 100 ml of ethanol and 10 ml of water, heat to dissolve, add activated carbon, stir for half an hour, then hot filtration, pass through a 0.45 um PTFE filter membrane, transfer the filtrate to a single-neck flask, heat to 70 °C, keep the temperature for 1.0 h, naturally cool to 10 °C, keep the temperature for 2 h with stirring, filter and dry to obtain white solid 13.0 g of sodium picosulfate with a yield of 75% and a purity of 99.9%. Isomer derivative impurities are not detected, as shown in Figure 3

[0059] According to the process of this example, the experiment was repeated 4 times to obtain 4 batches of API, and the clarity was qualified.

[0060] Example 2:

[0061] 1. Synthesis of 4,4'-(2-pyridinemethyl)-diphenol

[0062] Preparation: In a reaction flask, add trifluoroacetic acid (30 ml) and formic acid (70 ml) to form a mixed solution, then add phenol (100.0 g, 1.06 mol) and 2-pyridinecarboxaldehyde (50 g, 0.47 mol), stir at room temperature until completely dissolved, cool to 0 °C, and dropwise add concentrated sulfuric acid (50 g). After the dropwise addition is completed, heat to 40 °C and stir for 2 h. Cool to 5 °C, add 50 ml of water and 150 ml of ethanol, adjust pH = 7 with 20% sodium hydroxide solution, keep the temperature at 10 °C and stir for 2 h, filter, and rinse the filter cake with water to obtain crude 4,4'-(2-pyridinemethyl)-diphenol.

[0063] Refining: Transfer the crude 4,4'-(2-pyridinemethyl)-diphenol to a single-neck flask, add 300 ml of ethanol / formic acid isopropyl ester mixed solution (1:4) to heat and dissolve, dropwise add hydrochloric acid to adjust pH = 6, keep the temperature and stir for 2 h, cool to precipitate, keep the temperature at 5 °C for 1 h, filter, rinse the filter cake with a small amount of formic acid isopropyl ester, and dry to obtain white solid 90.6 g with a yield of 70% and a purity of 99.7%. Isomer impurity 2,4'-(2-pyridinemethyl)-diphenol is 0.02%.

[0064] 2. Synthesis of sodium picosulfate​

[0065] Preparation: In a reaction flask, add pyridine (400 ml), intermediate (80 g, 0.29 mol), sulfur trioxide pyridine complex (90 g, 0.56 mol), heat to 50 °C, keep the reaction for 14 h, after the reaction is completed, cool to 5 °C, add 400 ml water, adjust pH = 9 with 30% sodium hydroxide solution, extract with dichloromethane (300 ml x 2), store the organic phase, and the aqueous phase, concentrate the aqueous phase under reduced pressure to obtain a solid, add 640 ml of 90% ethanol / water solution, heat to reflux, hot filtration, cool the filtrate to crystallize, 5 °C filtration, wash the filter cake with a small amount of ethanol, to obtain crude sodium picosulfate.

[0066] Purification: Take the crude sodium picosulfate, add 1000 ml of ethanol and 100 ml of water, heat to dissolve, add activated carbon and stir, after half an hour, hot filtration, pass through a 0.22 um PTFE filter membrane, transfer the filtrate to a single-neck flask, heat to 70 °C, keep for 1.0 h, naturally cool to 10 °C, keep stirring for 2 h, filter and dry to obtain white solid 105.5 g of sodium picosulfate, yield 76%, purity 99.8%, no isomer derivative impurities detected, and the clarity is qualified.

[0067] According to the process of this example, repeat the experiment 5 times to obtain 5 batches of API, and the clarity is qualified.

[0068] Comparative Example 1:

[0069] 1. Synthesis of 4,4'-(2-pyridinemethylidene)-bisphenol

[0070] Preparation: In a reaction flask, add phenol (25.0 g), 2-pyridinecarboxaldehyde (10 g), heat and stir to dissolve, cool to 0 °C, add concentrated sulfuric acid (10 g) dropwise, after the addition is complete, the system is sticky and difficult to stir, keep stirring for 1 hour, heat to 30 °C, react for 3 h, cool to 5 °C, adjust pH = 7 with 30% sodium hydroxide solution, add 95% ethanol (60 ml), stir and filter, wash the filter cake with water. Transfer the filter cake to a reaction flask, add ethyl formate (40 ml), stir at 45 °C for 1 hour, hot filtration, wash the filter cake with ethyl formate (10 ml x 2), and dry to obtain white solid 13.6 g, yield 52%, related substances 97.8%, isomer impurities 2,4'-(2-pyridinemethylidene)-bisphenol 0.21%, as shown in Figure 4

[0071] 2. Synthesis of sodium picosulfate

[0072] ​Preparation: In a reaction flask, add acetonitrile (100 ml), intermediate (10 g, 0.04 mol), sulfur trioxide pyridine complex (16 g, 0.10 mol), heat to 50 °C, keep the reaction for 18 h, after the reaction is completed, pour the system into ice water (300 ml), adjust pH = 8 with sodium carbonate, extract with dichloromethane (100 ml x 4), store the organic phase, and the aqueous phase, the aqueous phase is concentrated under reduced pressure to obtain a solid, add 300 ml of 95% ethanol / water solution, heat to reflux, add activated carbon, reflux for half an hour, hot filtration, the filtrate is cooled to crystallize, 5 °C filtration, a small amount of 95% ethanol is used to rinse the filter cake, and sodium picosulfate crude product is obtained.

[0073] Refining: Take the sodium picosulfate crude product, add 200 ml of 95% ethanol, heat to reflux, add activated carbon, stir for half an hour, then hot filtration, cool the filtrate to room temperature, and then cool to 5 °C, keep stirring for 4 h, filter and dry to obtain white solid 9.7 g of sodium picosulfate, with a yield of 56%, a purity of 99.8%, isomer derivative impurities of 0.09%, and unqualified clarity.

[0074] Comparative Example 2

[0075] 1. Synthesis of 4,4'-(2-pyridylmethylene)-bisphenol

[0076] Preparation: In a reaction flask, add trifluoroacetic acid (7 ml), formic acid (14 ml) to form a mixed solution, then add phenol (20.0 g, 0.21 mol), 2-pyridinecarboxaldehyde (10 g, 0.09 mol), stir to dissolve at room temperature, cool to 0 °C, and drop 10 g of concentrated sulfuric acid. After the drop is completed, heat to 40 °C and stir for 2 h. Cool to 5 °C, add 10 m water and 30 ml of ethanol, adjust pH = 7 with 30% sodium hydroxide solution, keep stirring at 5-15 °C for 2 h, filter, and rinse the filter cake with water to obtain 4,4'-(2-pyridylmethylene)-bisphenol crude product.

[0077] Refining: Transfer the 4,4'-(2-pyridylmethylene)-bisphenol crude product into a single-neck flask, add 50 ml of ethanol / formic acid isopropyl ester mixed solution (1:5) to heat and dissolve, drop hydrochloric acid to adjust pH = 5, keep stirring for 2 h, cool to crystallize, keep at 5 °C for 1 h, filter, rinse the filter cake with a small amount of formic acid isopropyl ester, and dry to obtain white solid 17.8 g, with a yield of 69%, a purity of 99.8%, and isomer impurities of 2,4'-(2-pyridylmethylene)-bisphenol 0.03%.

[0078] 2. Synthesis of sodium picosulfate

[0079] Preparation: In a reaction bottle, add pyridine (50 ml), intermediate (10 g, 0.04 mol), sulfur trioxide pyridine complex (10 g, 0.06 mol), heat to 50°C, keep reaction for 12 h, after reaction, cool to 5°C, add 50 ml water, adjust pH = 9 with 30% sodium hydroxide solution, extract with dichloromethane (50 ml x 2), store the organic phase, and the aqueous phase, concentrate the aqueous phase under reduced pressure to obtain a solid, add 70 ml of 90% ethanol / water solution, heat to reflux, hot filtration, cool the filtrate to crystallize, filter at 5°C, wash the filter cake with a small amount of ethanol, and obtain crude sodium picosulfate.

[0080] Refining: Take crude sodium picosulfate, add 100 ml of ethanol and 10 ml of water, heat to dissolve, add activated carbon and stir, after half an hour, hot filtration, transfer the filtrate to a single-neck flask, heat to 70°C, keep for 1.0 h, naturally cool to 10°C, keep stirring for 2 h, filter and dry to obtain white solid 12.8 g of sodium picosulfate, yield 74%, purity 99.6%, no isomer derivative impurities detected, and the clarity is unqualified.

[0081] According to the process of the present comparative example, repeat the experiment 4 times to obtain 4 batches of API, test the clarity, 2 batches are qualified, and 2 batches are unqualified.

[0082] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Those skilled in the art can make various modifications and changes to the present application. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of sodium picosulphate, characterised in that, The 4,4'-(2-pyridylmethylene)-diphenol crude product is obtained by using phenol and 2-pyridine formaldehyde as raw materials, trifluoroacetic acid and formic acid as reaction solvents, dropwise adding concentrated sulfuric acid at 0-5 DEG C, and then heating to 30-50 DEG C to react, and then the 4,4'-(2-pyridylmethylene)-diphenol crude product is refined to obtain 4,4'-(2-pyridylmethylene)-diphenol pure product; The 4,4'-(2-pyridylmethylene)-diphenol crude product is obtained by using phenol and 2-pyridine formaldehyde as raw materials, trifluoroacetic acid and formic acid as reaction solvents, dropwise adding concentrated sulfuric acid at 0-5 DEG C, and then heating to 30-50 DEG C to react, and then the 4,4'-(2-pyridylmethylene)-diphenol crude product is refined to obtain 4,4'-(2-pyridylmethylene)-diphenol pure product; The process of intermediate refining is that: the mixture of alcohol organic matter and formate organic matter is used as refining solvent, the 4,4'-(2-pyridylmethylene)-diphenol crude product is added into the refining solvent and heated to dissolve, acid is added to adjust pH to 4.5-6.5, and then the temperature is lowered to crystallize, and then filtered. The alcohol organic matter is ethanol, isopropyl alcohol or n-propanol, and the formate organic matter is isopropyl formate, butyl formate, ethyl formate or methyl formate. The process of product refining is that: the piroctone olamine crude product is added into ethanol aqueous solution and heated to dissolve, then activated carbon is added and stirred, then hot filtration is carried out, the filtrate of hot filtration is filtered through PTFE filter membrane, the filtrate after filtering the filter membrane is heated to 65-75 DEG C, then the temperature is lowered to 0-20 DEG C to crystallize, and then filtered and dried. The volume ratio of ethanol to water in the ethanol aqueous solution is 4-10:

1.

2. The process for preparing sodium picosulphate according to claim 1, wherein the process is characterized by, The molar ratio of 2-pyridine formaldehyde to phenol is 1:2.1-3.

0. Or, the ratio of trifluoroacetic acid to formic acid is 1:1-4. Or, the volume ratio of reaction solvent to 2-pyridine formaldehyde is 1:1-5. Or, the weight ratio of concentrated sulfuric acid to 2-pyridine formaldehyde is 1:0.5-2.

3. The process for preparing sodium picosulphate as claimed in claim 2 wherein, The molar ratio of 2-pyridine formaldehyde to phenol is 1:2.2-2.

4.

4. The process for preparing sodium picosulphate as claimed in claim 2, wherein, The ratio of trifluoroacetic acid to formic acid is 1:1.5-2.

5.

5. The method for preparing sodium picosulfate as described in claim 2, characterized in that, The volume ratio of reaction solvent to 2-pyridine formaldehyde is 1:1.5-2.

5.

6. The process for preparing sodium picosulphate as claimed in claim 2, wherein, The weight ratio of concentrated sulfuric acid to 2-pyridine formaldehyde is 1:0.8-1.

2.

7. The process for preparing sodium picosulphate as claimed in claim 1 wherein, After dropwise adding concentrated sulfuric acid, the temperature is heated to 38-42 DEG C to react. ​ Or, the reaction time for preparing 4,4'-(2-pyridylmethylene)-diphenol is 2-8 h.

8. The process for preparing sodium picosulphate as claimed in claim 1 wherein, After the phenol and 2-pyridine formaldehyde are completely reacted, the temperature is lowered to 3-7 DEG C, ethanol aqueous solution is added, the pH is adjusted to neutral by adding alkali, and then stirred at 5-15 DEG C, filtered, and then the filter cake is washed with water to obtain 4,4'-(2-pyridylmethylene)-diphenol crude product. ​ 9. The process for preparing sodium picosulphate as claimed in claim 1 wherein, The refining solvent is a mixed solvent of ethanol and isopropyl formate. ​ Or, the acid for adjusting pH is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid and oxalic acid.

10. The process for preparing sodium picosulphate as claimed in claim 9 wherein, The acid for adjusting pH is hydrochloric acid. ​ 11. The process for preparing sodium picosulphate as claimed in claim 1 wherein, In the process of intermediate refining, the pH is adjusted to 5-6.

12. The process for preparing sodium picosulphate as claimed in claim 1 wherein, The weight ratio of sulfur trioxide pyridine complex to 4,4'-(2-pyridylmethylene)-diphenol pure product is 1:0.5-1.

5. Or, the temperature of sulfonation reaction is 45-55 DEG C, and the reaction time is 10-14 h.

13. The process for preparing sodium picosulphate as claimed in claim 12 wherein, The weight ratio of the sulfur trioxide pyridine complex to the pure 4,4'-(2-pyridylmethylene)-bisphenol is 1:0.8-1.

2.

14. The process for preparing sodium picosulphate as claimed in claim 1 wherein, The process of the base neutralization reaction is as follows: after the sulfonation reaction, the material is cooled to 3-7 ℃, water and sodium hydroxide solution are added, and the pH is adjusted to 8-10; ​ Or, after the base neutralization reaction, dichloromethane is used for extraction, the extracted aqueous phase is concentrated under reduced pressure to obtain a solid, the solid is added to an ethanol aqueous solution, heated to reflux, hot filtered, the filtrate is cooled to crystallize, filtered at 4-6 ℃, and a crude sodium picosulfate product is obtained.

15. The process for preparing sodium picosulphate as claimed in claim 1 wherein, In the product refining process, the volume ratio of ethanol to water in the ethanol aqueous solution is 8-10:1; Or, in the product refining process, the filtrate after the filter membrane filtration is heated to 65-75 ℃, and the temperature is maintained for 0.5-2 h; Or, in the product refining process, the crystallization time is 1-3 h.

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