Preparation method of methylene disalicylic acid

Abstract

The invention discloses a preparation method of methylene disalicylic acid, relates to the technical field of preparation of methylene disalicylic acid, and has the advantages that the methylene disalicylic acid prepared by the preparation method is high in conversion rate, a final product is low in polymer content and relatively high in chromatographic purity, and the product can be used as an intermediate for medicines. Similar derivatives are produced by adjusting the process for synthesis of bacitracin or other chemical materials; modularized production is flexible, the process is mature, skin and eye protection is paid attention to in the process, the preparation process of the method is high in safety, and solvent recycling and low-toxicity process design meet the green production requirement; according to the method, modular and standardized production can be adopted, the technological process is simplified, the equipment investment cost is reduced, low-toxicity solvents such as recyclable starch hydrolysate or corn fermentation products are used, environmental pollution is reduced, and the preparation quality of the method is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of methylene bis-salicylic acid, and specifically to a preparation method of methylene bis-salicylic acid. Background Art

[0002] Methylene bis-salicylic acid is an organic aromatic acid, mainly used as a raw material for high-grade coatings and a complexing agent for polypeptide antibiotic bacitracin. It is usually a white crystalline powder. The structural feature of methylene bis-salicylic acid is that the molecule is composed of two salicylic acid molecules connected by a methylene bridge. This structure endows it with some unique chemical and physical properties. The two salicylic acid units are connected by a methylene group, making the molecule have a certain rigidity and spatial configuration, while retaining the active groups such as phenolic hydroxyl and carboxyl groups of salicylic acid.

[0003] Methylene bis-salicylic acid can be mainly used in the medical field. It has antipyretic and analgesic effects similar to salicylic acid drugs, and can be used to relieve mild to moderate pain, such as headache, toothache, neuralgia, muscle pain, dysmenorrhea and joint pain, etc., and can also be used for the treatment of symptoms such as cold and fever; it has anti-inflammatory effects and can be used to treat inflammatory diseases such as rheumatoid arthritis, and can improve symptoms such as joint swelling and pain. In other fields, methylene bis-salicylic acid can also be used as an organic synthesis intermediate for the preparation of other organic compounds. In the synthesis of certain polymer materials, it may also be used as a functional monomer or additive to improve the performance of the materials.

[0004] In the prior art, it is usually to use salicylic acid and paraformaldehyde and under the catalysis of sulfuric acid to synthesize methylene bis-salicylic acid. However, due to the low solubility of salicylic acid in water, the chemical reaction is incomplete, which in turn leads to a low conversion rate of salicylic acid. Moreover, since the reaction temperature reaches 100 °C, the content of polymers in the final product is relatively high, resulting in low purity of methylene bis-salicylic acid and low safety in the preparation process.

[0005] In view of the above problems, a preparation method of methylene bis-salicylic acid is proposed. Summary of the Invention

[0006] The purpose of the present invention is to provide a preparation method of methylene bis-salicylic acid. By using this device to work, it solves the problems in the existing technology that it is usually to use salicylic acid and paraformaldehyde and under the catalysis of sulfuric acid to synthesize methylene bis-salicylic acid. However, due to the low solubility of salicylic acid in water, the chemical reaction is incomplete, which in turn leads to a low conversion rate of salicylic acid. Moreover, since the reaction temperature reaches 100 °C, the content of polymers in the final product is relatively high, resulting in low purity of methylene bis-salicylic acid and low safety in the preparation process.

[0007] To achieve the above object, the present invention provides the following technical solution: A preparation method of methylene bis-salicylic acid, characterized by comprising the following steps:

[0008] Step 1: First, mix and react the raw materials. Mix salicylic acid and paraformaldehyde in a molar ratio of 1:0.55 - 0.62, and continuously react at 92 °C for 13.5 hours to generate the target product, that is, generate 5,5'-methylene bis-salicylic acid. During the reaction process, mixing and stirring are required, and at the same time, the temperature and reaction time are controlled to avoid the formation of polymers. Then, add an appropriate amount of inorganic acid to the mixture and continue mixing and stirring until the chemical reaction is completed;

[0009] Step 2: Cooling and filtration. After the reaction is completed, cool the mixture to 28–36 °C, filter to obtain the methylene bis-salicylic acid filter cake, and the methylene bis-salicylic acid filter cake is washed with hot water and then dried to reduce the residue of by-products;

[0010] Step 3: Purification treatment can be carried out. The operator can carry out complexation and extraction. Treat with a metal salt complexing agent and combine with a low-toxic solvent, such as starch hydrolyzate or corn fermentation product, for extraction to improve the purity of the product;

[0011] Step 4: The operator needs to optimize the solvent ratio and temperature parameters, and the total yield can reach more than 92%, and the biological potency can reach more than 52 u / mg;

[0012] Step 5: Concentration and drying. After the extract is concentrated under reduced pressure, low temperature is used for drying, such as freeze-drying or vacuum drying methods, to obtain the finished product of methylene bis-salicylic acid. By adjusting the drying conditions, the crystals are optimized, and a solvent recovery process, such as distillation, is used to reduce waste emissions to obtain the product.

[0013] Preferably, during the synthesis process of Step 1, by adjusting the raw material ratio and reaction parameters, the reaction temperature is controlled at 58 - 70 °C without adding inorganic acid, and at 50 - 82 °C after adding organic acid; the material mixing and reaction time is 3.5 - 8.5 hours.

[0014] Preferably, in Step 1, salicylic acid needs to be first dissolved in an organic acidic solvent, and then paraformaldehyde solvent is added. The mixing ratio of salicylic acid and the organic acidic solvent is 1:1.8 - 3.5 weight / volume ratio, and the addition amount of inorganic acid is 4% of the volume of the organic acidic solvent.

[0015] Preferably, the mixing ratio of salicylic acid and paraformaldehyde in Step 1 is 1:0.65 - 0.86 molar ratio, and at the same time, the addition amount of inorganic acid in Step 1 should be 4.5 - 5.5% of the volume of the organic acidic solvent.

[0016] Preferably, the organic acid solvent in the first step is composed of a combined organic acid mixture of formic acid with a concentration of 90%-93%, acetic acid with a concentration of 88%-92%, and propionic acid with a concentration of 87%-91%.

[0017] Preferably, the inorganic acid in the first step is composed of a combined inorganic acid mixture of hydrochloric acid with a concentration of 28%-32% and sulfuric acid with a concentration of 92%-95%.

[0018] Preferably, in the first step, the operator can use a modular stirring tank, which is equipped with a temperature control system and a multi-valve discharge port to achieve the purpose of standardized operation, facilitating industrial scale-up; the equipment connecting pipes and the cooling extraction tank used in the second step are made of stainless steel, equipped with a micro water pump and an electronic valve to precisely control the flow of the reaction solution, jointly making fine adjustments to the preparation equipment, and improving the preparation quality of methylene bis-salicylic acid.

[0019] Preferably, in steps one to five, higher requirements for safety and environmental protection are needed. When operating, the operator needs to wear protective equipment, such as gloves, goggles and other important protective equipment, to avoid direct contact with the raw materials.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] A preparation method of methylene bis-salicylic acid proposed in this application has the following advantages compared with the prior art. The methylene bis-salicylic acid prepared by the preparation method has a high conversion rate, a low content of polymers in the final product, a relatively high chromatographic purity. The product can be used as an intermediate for drugs, such as bacitracin or other chemical materials synthesis, and similar derivatives can be produced by adjusting the process; the modular production of the present invention is flexible and the process is mature. Skin and eye protection are noted during the process, and the preparation process of this method has high safety. The solvent recovery and utilization and the low-toxic process design meet the requirements of green production; and this method can adopt modular and standardized production, simplify the process flow, reduce the equipment investment cost, use low-toxic solvents, such as recyclable starch hydrolyzate or corn fermentation products, reduce environmental pollution, and improve the quality of the product prepared by the method of the present invention. Description of the Drawings

[0022] Figure 1 It is a flow chart of the steps of the preparation method of methylene bis-salicylic acid of the present invention. Detailed Embodiments

[0023] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0024] To further understand the content of the present invention, the present invention will be described in detail with reference to the accompanying drawings.

[0025] Combined with Figure 1 , a preparation method of methylene bis-salicylic acid includes the following steps:

[0026] Step 1: First, mix and react the raw materials. Mix salicylic acid and paraformaldehyde in a molar ratio of 1:0.55 - 0.62, and continuously react at 92 °C for 13.5 hours to generate the target product, that is, generate 5,5'-methylene bis-salicylic acid. During the reaction process, mixing and stirring are required, and at the same time, the temperature and reaction time are controlled to avoid the formation of polymers; then add an appropriate amount of inorganic acid to the mixture and continue mixing and stirring until the chemical reaction is completed;

[0027] Step 2: Cooling and filtration. After the reaction is completed, cool the mixture to 28–36 °C, filter to obtain the methylene bis-salicylic acid filter cake, and the methylene bis-salicylic acid filter cake is washed with hot water and then dried to reduce the residue of by-products;

[0028] Step 3: Purification treatment can be carried out. The operator can carry out complexation and extraction. Treat with a metal salt complexing agent and combine with a low-toxic solvent, such as starch hydrolyzate or corn fermentation product, for extraction to improve the purity of the product;

[0029] Step 4: The operator needs to optimize the solvent ratio and temperature parameters, and the total yield can reach more than 92%, and the biological potency can reach more than 52 u / mg;

[0030] Step 5: Concentration and drying. After the extract is concentrated under reduced pressure, low temperature is used for drying, such as freeze-drying or vacuum drying methods, to obtain the finished product of methylene bis-salicylic acid. By adjusting the drying conditions, the crystals are optimized, and a solvent recovery process, such as distillation method, is used to reduce waste emissions to obtain the product.

[0031] During the synthesis process of Step 1, by adjusting the raw material ratio and reaction parameters, the reaction temperature can be controlled at 58 - 70 °C when no inorganic acid is added, and at 50 - 82 °C after adding organic acid; the mixing reaction time of the materials is 3.5 - 8.5 hours.

[0032] In Step 1, salicylic acid needs to be first dissolved in an organic acidic solvent, and then paraformaldehyde solvent is added. The mixing ratio of salicylic acid and the organic acidic solvent is 1:1.8 - 3.5 weight / volume ratio, and the addition amount of inorganic acid is 4% of the volume of the organic acidic solvent.

[0033] In Step 1, the mixing ratio of salicylic acid and paraformaldehyde is 1:0.65 - 0.86 molar ratio, and at the same time, the addition amount of inorganic acid in Step 1 should be 4.5 - 5.5% of the volume of the organic acidic solvent.

[0034] In Step 1, the organic acid solvent is composed of formic acid with a concentration of 90%-93%, acetic acid with a concentration of 88%-92%, and propionic acid with a concentration of 87%-91% mixed together as the organic acid.

[0035] In Step 1, the inorganic acid is composed of hydrochloric acid with a concentration of 28%-32% and sulfuric acid with a concentration of 92%-95% mixed together as the inorganic acid.

[0036] In Step 1, the operator can use a modular stirring tank, which is equipped with a temperature control system and a multi-valve discharge port to achieve the purpose of standardized operation, facilitating industrial scale-up; in Step 2, the equipment connecting pipes and the cooling extraction pool used are made of stainless steel, and are combined with a micro water pump and an electronic valve to precisely control the flow of the reaction solution, jointly making fine adjustments to the preparation equipment, and improving the preparation quality of methylene bis-salicylic acid.

[0037] From Step 1 to Step 5, requirements for safety and environmental protection need to be improved. When operating, the operator needs to wear protective equipment such as gloves and goggles to avoid direct contact with the raw materials.

[0038] The present invention will be further described below in conjunction with embodiments.

[0039] Example 1:

[0040] Other simple implementation methods for preparing methylene bis-salicylic acid:

[0041] Directly mix salicylic acid and formaldehyde in a molar ratio of 1:0.58, react at 90-95°C for 12-14 hours. Without complex solvents or catalysts, after the reaction is completed, cool the mixture to 25–30°C and then directly filter without multiple washings, reducing solvent consumption;

[0042] Extract with a low-toxic solvent such as starch hydrolyzate, omitting the complex complexation step, and complete the reaction, cooling and filtration through a single container, reducing equipment complexity;

[0043] Directly use vacuum drying to treat the product, omitting the concentration step, reducing energy consumption by 40%. This method is suitable for small and medium-scale production. The above methods comprehensively optimize the reaction time, equipment requirements and post-treatment process, taking into account both efficiency and environmental protection.

[0044] Example 2:

[0045] A method for preparing methylene bis-salicylic acid different from Example 1:

[0046] Prepare salicylic acid, formaldehyde solution (38%-45%), concentrated sulfuric acid, toluene, anhydrous ethanol;

[0047] In a three-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, a certain amount of salicylic acid and an appropriate amount of toluene were added. Stir and heat until the salicylic acid is completely dissolved. Toluene serves as a solvent, which helps control the reaction temperature and dissolve the reactants.

[0048] Control the temperature in the three-necked flask at 55 - 66 °C, and slowly dropwise add a moderate amount of formaldehyde solution. It undergoes a condensation reaction with salicylic acid. The dropping rate should be controlled properly to avoid too violent a reaction.

[0049] After dropping the formaldehyde solution, add an appropriate amount of concentrated sulfuric acid to the material as a catalyst. Concentrated sulfuric acid can accelerate the condensation reaction between salicylic acid and formaldehyde, improve the reaction rate and yield. When adding concentrated sulfuric acid, it is necessary to prevent the concentrated sulfuric acid from splashing out.

[0050] Under stirring conditions, keep the reaction mixture at 80 - 90 °C. The reflux reaction can ensure sufficient contact and reaction of the reactants, improve the conversion rate of the reaction. Through the reflux condenser, the volatilized reactants and solvents can return to the reaction system, reducing material loss.

[0051] Cool the reaction mixture to room temperature, and then slowly add an appropriate amount of sodium carbonate solution or sodium hydroxide solution for neutralization to make the pH value of the reaction solution reach 7 - 8. Transfer the neutralized reaction solution to a separatory funnel and add an appropriate amount of organic solvent for extraction.

[0052] Then concentrate and crystallize the extracted product to precipitate methylene bis-salicylic acid in the form of pure crystals. Separate the crystallized product by filtration and wash the crystals with a small amount of cold ethanol to remove the residual impurities on the surface. Finally, dry it at an appropriate temperature to obtain a pure methylene bis-salicylic acid product.

[0053] In summary: A preparation method of methylene bis-salicylic acid proposed in this application. Compared with the prior art, the advantages of the present invention are that the methylene bis-salicylic acid prepared by the preparation method has a high conversion rate, a small content of polymers in the final product, a relatively high chromatographic purity. The product can be used as an intermediate for drugs, such as bacitracin or other chemical materials synthesis, and similar derivatives can be produced by adjusting the process. The modular production of the present invention is flexible and the process is mature. Skin and eye protection should be noted during the process, and the preparation process of this method is highly safe. The solvent recovery and utilization and low-toxic process design meet the requirements of green production. And this method can adopt modular and standardized production, simplify the process flow, reduce the equipment investment cost, use low-toxic solvents, such as recyclable starch hydrolysates or corn fermentation products, reduce environmental pollution, and improve the quality of the product prepared by the method of the present invention.

[0054] It should be noted that, in this document, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variation thereof is intended to cover non-exclusive inclusion, such that a process, method, article or device comprising a series of elements not only includes those elements but also includes other elements not expressly listed, or elements inherent to such process, method, article or device.

[0055] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing methylene bis(salicylic acid), characterized in that, It includes the following steps: Step 1: First, mix and react the raw materials. Mix salicylic acid and paraformaldehyde in a molar ratio of 1:0.55 - 0.62, and continuously react at 92°C for 13.5 hours to generate the target product, that is, 5,5'-methylenebis(salicylic acid). During the reaction process, mixing and stirring are required, and at the same time, the temperature and reaction time are controlled to avoid the formation of polymers. Then, add an appropriate amount of inorganic acid to the mixture and continue mixing and stirring until the chemical reaction is completed; Step 2: Cooling and filtration. After the reaction is completed, cool the mixture to 28–36°C, filter to obtain the methylenebis(salicylic acid) filter cake, and the methylenebis(salicylic acid) filter cake is washed with hot water and then dried to reduce the residual by-products; Step 3: Purification treatment can be carried out. The operator can carry out complexation and extraction. Through treatment with a metal salt complexing agent and combined with a low-toxic solvent, such as starch hydrolyzate or corn fermentation product, for extraction to improve the purity of the product; Step 4: The operator needs to optimize the solvent ratio and temperature parameters, and the total yield can reach more than 92%, and the biological potency can reach more than 52 u / mg; Step 5: Concentration and drying. After the extraction solution is decompressed and concentrated, low temperature is used for drying, such as freeze-drying or vacuum drying methods, to obtain the finished product of methylenebis(salicylic acid). By adjusting the drying conditions, the crystals are optimized, and a solvent recovery process, such as distillation, is used to reduce waste emissions to obtain the product.

2. The preparation method of methylene bis-salicylic acid according to claim 1, wherein: During the synthesis process of Step 1, by adjusting the raw material ratio and reaction parameters, the reaction temperature is controlled at 58 - 70°C when no inorganic acid is added, and the temperature is controlled at 50 - 82°C after adding the organic acid; the material mixing and reaction time is 3.5 - 8.5 hours.

3. The preparation method of methylene bis(salicylic acid) according to claim 1, characterized in that: In Step 1, salicylic acid needs to be first dissolved in an organic acidic solvent, and then paraformaldehyde solvent is added. The mixing ratio of salicylic acid and the organic acidic solvent is 1:1.8 - 3.5 weight / volume ratio, and the addition amount of the inorganic acid is 4% of the volume of the organic acidic solvent.

4. A method for preparing methylene bis(salicylic acid) according to claim 1, characterized in that: The mixing ratio of salicylic acid and paraformaldehyde in Step 1 is 1:0.65 - 0.86 molar ratio, and at the same time, the addition amount of the inorganic acid in Step 1 should be 4.5 - 5.5% of the volume of the organic acidic solvent.

5. The preparation method of methylene bis(salicylic acid) according to claim 1, characterized in that: The organic acidic solvent in Step 1 is composed of formic acid with a concentration of 90% - 93%, acetic acid with a concentration of 88% - 92%, and propionic acid with a concentration of 87% - 91% mixed together as the organic acid.

6. The preparation method of methylene bis-salicylic acid according to claim 1, characterized in that: The inorganic acid in Step 1 is composed of hydrochloric acid with a concentration of 28% - 32% and sulfuric acid with a concentration of 92% - 95% mixed together as the inorganic acid.

7. The preparation method of methylene bis-salicylic acid according to claim 1, characterized in that: In Step 1, the operator can use a modular stirring tank, which is equipped with a temperature control system and multiple valve outlets to achieve the purpose of standardized operation and facilitate industrial scale-up; the equipment connecting pipes and cooling extraction tanks used in Step 2 are made of stainless steel, equipped with a micro water pump and electronic valves to precisely control the flow of the reaction solution, and jointly make fine adjustments to the preparation equipment to improve the preparation quality of methylenebis(salicylic acid).

8. A method for preparing methylene bis(salicylic acid) according to claim 1, characterized in that: In Steps 1 to 5, requirements for safety and environmental protection need to be improved. The operator needs to wear protective equipment, such as gloves, goggles and other important protective equipment during operation to avoid direct contact with the raw materials.

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