Preparation method of S-carboxymethyl-L-cysteine sulfone

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of S-carboxymethyl-L-cysteine sulfone. The method comprises the following steps: 1) dispersing an inorganic alkaline reagent in a solvent, uniformly mixing, adding raw materials in batches until the solution is clarified, cooling the solution, dropwise adding an oxidant, and slowly heating for reaction; 2) after the reaction is completed, adding an acid solution for acidification, performing low-temperature treatment to obtain a crystal, performing suction filtration to obtain a filter cake, and drying, grinding and drying the filter cake to obtain a crude product; and 3) adding a solvent into the crude product, pulping, carrying out suction filtration to obtain a filter cake, carrying out solvent leaching on the filter cake, drying, grinding into powder, and further drying to obtain the product. According to the method provided by the invention, carbocisteine is oxidized into S-carboxymethyl-L-cysteine sulfone in one step under the condition of an oxidizing agent without a catalyst.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing S-carboxymethyl-L-cysteine ​​sulfone. Background Art

[0002] Carbocysteine, also known as S-(carboxymethyl)cysteine ​​(S-Carboxymethyl-L-cysteine), has a molecular formula of C5H9NO4S and is an important expectorant and antitussive drug. There are many production processes for carbocysteine. Currently, the most direct synthesis reaction is to use cysteine ​​hydrochloride and chloroacetic acid as raw materials for carboxylation reaction under weak alkaline conditions, and the commonly used process requires two crystallization purifications to produce qualified products.

[0003] Carbocysteine ​​is highly hygroscopic and easy to aggregate. Its molecule contains thioguanidine groups. During its production and storage, it is easy to produce sulfoxide and sulfone impurities, which not only affect the purity of the drug, but also easily change the molecular structure and pharmacological and toxicological characteristics, thereby affecting the stability and efficacy of the drug, and even endangering human health. The sulfone impurity of carbocysteine ​​is mainly S-carboxymethyl-L-cysteine ​​sulfone (25515-73-5). After carbocysteine ​​is further oxidized to S-carboxymethyl-L-cysteine ​​sulfone, its hygroscopicity is further enhanced, making it difficult to form a stable solid substance. The powder has poor fluidity, which is not conducive to long-term storage. Some products will be lost or contaminated during use.

[0004] The content of sulfone impurity S-carboxymethyl-L-cysteine ​​sulfone is the main factor affecting the purity of carbocysteine, and has an important impact on the quality and safety of drugs. It is necessary to prepare high-purity sulfone impurities to detect and analyze the sulfone impurity content in the drug carbocysteine ​​to be tested, which can ensure the quality of the drug and protect the health and safety of the drug users. In addition, there is currently no technology that can prepare S-carboxymethyl-L-cysteine ​​sulfone with controllable appearance and morphology.

[0005] In order to solve the above problems, it is necessary to develop a new preparation method for S-carboxymethyl-L-cysteine ​​sulfone. Summary of the invention

[0006] Based on the above content, in order to solve the problems of complex operation, complex catalytic system, low product purity and uncontrollable product morphology in the prior art for preparing high-purity S-carboxymethyl-L-cysteine ​​sulfone, the present invention proposes a method for preparing S-carboxymethyl-L-cysteine ​​sulfone.

[0007] The objects of the present invention are: First, to provide a method for preparing S-carboxymethyl-L-cysteine ​​sulfone under mild conditions; 2. Simplify the operation of the preparation method; 3. Improve the purity of S-carboxymethyl-L-cysteine ​​sulfone.

[0008] To achieve the above objectives, the present invention adopts the following technical solutions.

[0009] A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, The method comprises: 1) Disperse the inorganic alkaline reagent in the solvent and mix evenly, add the raw materials in batches until the solution is clear, cool the solution, add the oxidant dropwise, and slowly heat it to react; 2) After the reaction is completed, add acid solution for acidification, then perform low temperature treatment to obtain crystals, filter to obtain filter cakes, dry, grind, and dry the filter cakes to obtain a crude product; 3) Add solvent to the crude product for slurrying, obtain filter cake by suction filtration, wash the filter cake with solvent, dry it, grind it into powder and further dry it to obtain the product.

[0010] As a preference, Step 1) the inorganic alkaline reagent is sodium bicarbonate and / or potassium bicarbonate and / or sodium carbonate and / or potassium carbonate; Step 1) The solvent is water, and the amount used is 10-15 mL / g inorganic alkaline reagent; Step 1) The raw material is carbocysteine, and its usage is 2.1-2.2 g / g inorganic alkaline reagent.

[0011] As a preference, Step 1) The cooling treatment is to cool to -20 to -10 °C and maintain a constant temperature; Step 1) The oxidant is a hydrogen peroxide solution, the dosage of which is 0.43-0.52 mL / mL of solvent, first added dropwise at a rate of 0.25-0.35 mL / min, and then added dropwise at a rate of 0.50-0.60 mL / min; Step 1) The slow heating is to control the system to slowly heat up to 55-65°C by adding an oxidant dropwise and maintain a constant temperature; Step 1) The reaction is carried out at a constant temperature for 4 to 24 hours after the oxidant is added dropwise.

[0012] As a preference, Step 2) the acid solution is hydrochloric acid and / or sulfuric acid, the concentration of which is 3-6 g / L, and the pH value of the system is adjusted to 1-2; Step 2) The low temperature treatment is to crystallize at a constant temperature of -15 to -5 °C for 24 to 30 hours, keep stirring, and control the stirring speed to be lower than 15 RPM.

[0013] As a preference, Step 3) The process of adding solvent to pulp is as follows: Add 4-5 mL of water per gram of crude product, mix well, and beat for 5-10 minutes; Step 3) The solvent washing is washing the filter cake with water.

[0014] As a preference, The drying in step 2) and step 3) is performed by vacuum drying at 45-55°C for 1-4 hours.

[0015] In the technical solution of the present invention, carbocysteine ​​is oxidized to S-carboxymethyl-L-cysteine ​​sulfone in only one step. Since carbocysteine ​​contains two carboxyl groups, it is highly acidic, hydrogen peroxide is unstable, and oxygen is released quickly, resulting in a decrease in oxidizing ability. In an alkaline environment, carbocysteine ​​can be completely dissolved to form a homogeneous reaction, and the stability of the carbocysteine ​​oxidation reaction can be improved. Therefore, the present invention first constructs an alkaline environment by an inorganic alkaline reagent.

[0016] Meanwhile, since the rapid, one-time addition of carbocysteine ​​will cause its reunion, it is not conducive to dissolving, so the present invention feeds in batches. At high temperatures, the oxidation reaction of carbocysteine ​​is unstable, and the reaction is an exothermic reaction. Hydrogen peroxide decomposes rapidly at high temperatures, resulting in the generation of new impurities, which are difficult to separate from the sulfone and sulfoxide impurity structures with large polarity in subsequent operations. Therefore, the present invention cools the system.

[0017] In the oxidation reaction, other peroxides can be used instead of hydrogen peroxide, but multiple impurity peaks are found in the characterization, and the purity of the target product is low. Moreover, when hydrogen peroxide is used as an oxidant for the reaction, the products formed are water and oxygen, which have no effect on the reaction system, and there is no need to add a recovery device, which has little pressure on the environment and simplifies the operation. At the same time, the oxidation temperature has a great influence on the purity of the product. At too low a temperature, a substance mixed with raw materials will be formed, and the purity is extremely low; at too high a temperature, excessive oxidation will be obtained to obtain other by-products, which are also difficult to remove, affecting the purity of the target product S-carboxymethyl-L-cysteine ​​sulfone.

[0018] like Figure 1 As shown in the reaction formula, at this time, the two carboxylic acid groups of carbocysteine ​​and S-carboxymethyl-L-cysteine ​​sulfone are reacted into carboxylic acid sodium salt, and the target product cannot be obtained. Therefore, the present invention uses acid solution for acidification, and the system pH value significantly affects the crystal solubility. In this process, dibasic acid, such as sulfuric acid, can also be used, mainly to control the amount of acid solution according to the system pH value, thereby ensuring that the crystals are crystallized and separated out.

[0019] Furthermore, after a large number of crystals are precipitated, the crystal growing process is carried out under a supersaturation level that is easy to control. It is a dynamic equilibrium process, and the crystals with small particle size dissolve, making the crystal size more uniform. The crystals grow uniformly and have high purity, and less solution is adsorbed on their surface. Growing crystals under too high a temperature condition is not only easy to cause a rapid decrease in supersaturation, thereby slowing down the crystal growth rate, but also affects the solubility of the crystals, and even causes no obvious crystal precipitation.

[0020] In addition to controlling the pH and temperature during the crystal growing process, the present invention also controls the stirring speed. If the stirring speed is too fast, the difference between the saturation point temperature and the maximum supersaturation point temperature that can spontaneously nucleate will decrease, which is likely to cause secondary nucleation and reduce the crystal size.

[0021] The present invention obtains crystals with complete morphology, large size and uniform size by controlling various conditions of the crystal growing process. In the art, crystals are generally obtained by direct spin drying, but the materials in the system are very soluble in water, the product contains a large amount of bound water and inorganic salts, and the product is easy to absorb moisture and deteriorate, which is inconvenient to use. After the crystal is grown, the moisture can be removed by drying. In addition, since the properties of the crystal are relatively stable after formation and it is not easy to absorb moisture, the present invention can purify the crystal by pure water beating, and it is easier to dissolve the original impurities in the system.

[0022] The beneficial effects of the present invention are as follows: (1) The conditions in the method provided by the present invention are mild, and only acidification is required after the reaction, without consuming more other reagents, and the reagents used are cheap and readily available; (2) The method provided by the present invention does not require a catalyst and, under oxidizing conditions, carbocysteine ​​is oxidized in one step to S-carboxymethyl-L-cysteine ​​sulfone; (3) The only by-product in the preparation process of the present invention is low-toxic brine, the solvent residue is single and easy to remove, no organic solvent is needed for further treatment, the wastewater can be recycled and treated, and the pressure on the environment is small; (4) The S-carboxymethyl-L-cysteine ​​sulfone prepared by the present invention has high purity and can be directly used as a comparative product for detection and analysis; (5) The S-carboxymethyl-L-cysteine ​​sulfone solid prepared by the present invention is not easy to absorb moisture and is not easy to liquefy. It has stable properties and is easy to store and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : is the oxidation reaction formula of the embodiment. DETAILED DESCRIPTION

[0024] The present invention is further described in detail below in conjunction with specific embodiments and the accompanying drawings. A person of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by a person of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0025] Unless otherwise specified, the raw materials used in the examples of the present invention are all commercially available or available to those skilled in the art; unless otherwise specified, the methods used in the examples of the present invention are all methods known to those skilled in the art.

[0026] Unless otherwise specified, the CAS number of sodium bicarbonate used in the examples of the present invention is 144-55-8.

[0027] Unless otherwise specified, the CAS number of carbocysteine ​​used in the examples of the present invention is 5439-87-2.

[0028] Unless otherwise specified, the hydrogen peroxide solution used in the examples of the present invention has a CAS number of 7722-84-1 and a concentration of 50 wt%.

[0029] Embodiment 1: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 52 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 60°C by adding hydrogen peroxide solution, and the temperature is kept constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. The reaction is complete by HPLC. 2) After the reaction is completed, the pH value of the system is measured to be 2.8, and hydrochloric acid with a concentration of 6 g / L is added to adjust the pH value of the system to 1.5 for acidification, and then crystallize at a constant temperature of -10 ° C for 28 h, keep stirring, and control the stirring speed to 10 RPM to obtain crystals, and filter to obtain a filter cake, and place the filter cake at 50 ° C for vacuum drying for 2 h, grind the filter cake, and then vacuum dry it at 50 ° C for 1 h to obtain a crude product; 3) Add 4 mL of water per gram of crude product and mix evenly, then beat for 5 min, filter to obtain a filter cake, rinse the filter cake with water at a flow rate of 5 mL / min, transfer the filter cake to a weighing bottle, vacuum dry it at 50 °C for 2 h, grind it into powder and further dry it to obtain the product.

[0030] The crystals obtained in step 2) of this example are white spherical solids. After purification, 4.8481 g of white solid powder was obtained, and the purity was 99.20 wt% as determined by HPLC.

[0031] Embodiment 2: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 52 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 60°C by adding hydrogen peroxide solution, and the temperature is kept constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. The reaction is complete by HPLC. 2) After the reaction is completed, the pH value of the system is measured to be 2.8, and sulfuric acid with a concentration of 3 g / L is added to adjust the pH value of the system to 1.8 for acidification, and then crystallize at a constant temperature of -10 ° C for 28 h, keep stirring, and control the stirring speed to be lower than 10 RPM to obtain crystals, and filter to obtain a filter cake, and place the filter cake at 50 ° C for vacuum drying for 2 h, grind the filter cake, and then vacuum dry it at 50 ° C for 1 h to obtain a crude product; 3) Add 4 mL of water per gram of crude product and mix evenly, then beat for 5 min, filter to obtain a filter cake, rinse the filter cake with water at a flow rate of 5 mL / min, transfer the filter cake to a weighing bottle, vacuum dry it at 50 °C for 2 h, grind it into powder and further dry it to obtain the product.

[0032] After refining in this example, 3.1100 g of white solid powder was obtained, and the yield was low. Further, in this example, the filtrate was added with sulfuric acid at a concentration of 3 g / L to adjust the pH value of the system to 2.8, and the system was placed at -10 ° C for constant temperature crystallization for 50 h, and a large amount of white solid was precipitated. The solution was a white suspension, which was filtered, vacuum dried at 50 ° C for 2 h, ground, and combined with the white solid powder obtained by the above refining to obtain 4.9852 g of product. HPLC detection showed that its purity was 98.74 wt%.

[0033] Comparative Example 1: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 26 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 42°C by adding hydrogen peroxide solution. Keep the temperature constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. Use HPLC to detect the completion of the reaction. 2) After the reaction is completed, the pH value of the system is measured to be 6.5, and hydrochloric acid with a concentration of 6 g / L is added to adjust the pH value of the system to 3.4 for acidification, and then crystallize at a constant temperature of -15 ° C for 28 h, keep stirring, and control the stirring speed to be lower than 10 RPM to obtain crystals, and filter to obtain a filter cake, and place the filter cake at 50 ° C for vacuum drying for 2 h, grind the filter cake, and then vacuum dry it at 50 ° C for 1 h to obtain a crude product; 3) Add 4 mL of water per gram of crude product and mix evenly, then beat for 5 min, filter to obtain a filter cake, rinse the filter cake with water at a flow rate of 5 mL / min, transfer the filter cake to a weighing bottle, vacuum dry it at 50 °C for 2 h, grind it into powder and further dry it to obtain the product.

[0034] After refining, 5.2385 g of white solid powder was obtained, and the purity was 95.55 wt% after HPLC detection. The lower crystal growth temperature in this case resulted in a decrease in the molecular diffusion rate, a slower crystal growth rate, and uneven supersaturation in the solution, which caused differences in the growth rate of the crystals in different regions. It also increased the internal stress of the crystals and produced defects. In the subsequent treatment, impurities were introduced, resulting in a decrease in the purity of the product. In addition, at a low crystal growth temperature, the crystals formed had irregular morphology.

[0035] Comparative Example 2: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 26 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system temperature is controlled at 27°C by adding hydrogen peroxide solution. Keep the temperature constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h.

[0036] After HPLC detection, it was found that the reaction was incomplete. At a low oxidation temperature, the purity of carbocysteine ​​sulfone in the reaction solution was 92.65 wt%, and other impurities and carbocysteine ​​were detected, wherein the content of carbocysteine ​​was 1.51 wt%.

[0037] Comparative Example 3: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 26 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 42°C by adding hydrogen peroxide solution. Keep the temperature constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. Use TLC to detect whether the reaction is complete. 2) After the reaction is completed, the pH value of the system is measured to be 6.5, and 6 g / L hydrochloric acid is added to adjust the pH value of the system to 4.0 for acidification, and then crystallize at a constant temperature of -10 °C for 28 h, while maintaining stirring and controlling the stirring speed to be less than 10 RPM.

[0038] In this case, no solid was precipitated during the crystallization reaction process. Further extension of the crystallization time to 72 h did not produce any solid.

[0039] Only when the operation of "crystallizing at a constant temperature of -10 °C for 28 h" in the above step 2) was changed to "crystallizing at a constant temperature of -15 °C for 50 h", no solid was precipitated.

[0040] Carbocysteine ​​and S-carboxymethyl-L-cysteine ​​sulfone contain two carboxylic acid groups. According to Le Chatelier's principle, the dynamic equilibrium system of the molecules is affected by the increase in pH value, which drives more molecules to ionize, resulting in increased crystal solubility and making it difficult to precipitate crystals from the system.

[0041] Comparative Example 4: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 26 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 42°C by adding hydrogen peroxide solution. Keep the temperature constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. Use TLC to detect whether the reaction is complete. 2) After the reaction is completed, the pH value of the system is measured to be 6.5, and 6 g / L hydrochloric acid is added to adjust the pH value of the system to 1.0 for acidification, and then crystallize at a constant temperature of -10 °C for 28 h, while maintaining stirring and controlling the stirring speed to be less than 10 RPM.

[0042] In this case, no solid was precipitated during the crystallization reaction process. Further extension of the crystallization time to 72 h did not produce any solid.

[0043] Only when the operation of "crystallizing at a constant temperature of -10 °C for 28 h" in the above step 2) was changed to "crystallizing at a constant temperature of -15 °C for 50 h", no solid was precipitated.

[0044] According to the above results, when the pH value of the system is too low, the amino groups in carbocysteine ​​and S-carboxymethyl-L-cysteine ​​sulfone form salts, which increases the solubility of crystals. In an acidic environment, solute molecules are more likely to combine with hydrogen ions, reducing the content of crystallizable substances. In addition, excessive hydrogen ions hinder the migration of solute molecules, making it difficult for crystals to form.

[0045] Comparative Example 5: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 26 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 42°C by adding hydrogen peroxide solution. Keep the temperature constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. Use TLC to detect whether the reaction is complete. 2) After the reaction is completed, the pH value of the system is measured to be 6.5, and 6 g / L hydrochloric acid is added to adjust the pH value of the system to 1.0 for acidification, and then crystallization is carried out at a constant temperature of -20 °C for 28 h, while maintaining stirring and controlling the stirring speed to be less than 10 RPM.

[0046] During the crystallization process, the entire system froze and could not continue crystallization.

[0047] Comparative Example 6: A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, the method comprising: 1) Disperse 9.4 g of sodium bicarbonate in 100 mL of water and mix well. Add a total of 20 g of carbocysteine ​​in five batches, adding 4 g of carbocysteine ​​in each batch and mix well until the solution is clear. Transfer the system to a low-temperature reaction tank and cool it to -15°C. Keep the temperature constant. At the same time, add 26 mL of hydrogen peroxide solution through a constant pressure dropping funnel. First, add it at a rate of 0.25 mL / min, and then at a rate of 0.50 mL / min. The system is slowly heated to 42°C by adding hydrogen peroxide solution. Keep the temperature constant. After the hydrogen peroxide solution is added, react at a constant temperature for 6.5 h. Use TLC to detect whether the reaction is complete. 2) After the reaction is completed, the pH value of the system is measured to be 6.5, and 6 g / L hydrochloric acid is added to adjust the pH value of the system to 1.0 for acidification, and then the solution is crystallized at a constant temperature of 0 °C for 28 h, while stirring is maintained and the stirring speed is controlled to be lower than 10 RPM.

[0048] In this example, no solid was obviously precipitated during the crystallization reaction process. The crystallization time was further extended to 72 h, and no solid was precipitated. At an excessively high crystallization temperature, the viscosity of the solution is low, and the solute molecules can move freely, which increases the difficulty of overcoming the nucleation barrier. In addition, the solution molecules move at a faster speed, resulting in poor interactions between the solute molecules, and it is impossible to effectively form a crystal nucleus. Even if a crystal nucleus is formed, it will dissolve due to the high temperature. It can be seen that the reaction is highly sensitive to the system pH value and the crystallization temperature, so the present invention strictly controls the various parameters of the reaction.

Claims

1. A method for preparing S-carboxymethyl-L-cysteine ​​sulfone, characterized in that: The method comprises: 1) Disperse the inorganic alkaline reagent in the solvent and mix evenly, add the raw materials in batches until the solution is clear, cool the solution, add the oxidant dropwise, and slowly heat it to react; 2) After the reaction is completed, add acid solution for acidification, then perform low temperature treatment to obtain crystals, filter to obtain filter cakes, dry, grind and dry the filter cakes to obtain a crude product; 3) Add solvent to the crude product for slurrying, obtain filter cake by suction filtration, wash the filter cake with solvent, dry it, grind it into powder and further dry it to obtain the product.

2. The method for preparing S-carboxymethyl-L-cysteine ​​sulfone according to claim 1, characterized in that: Step 1) the inorganic alkaline reagent is sodium bicarbonate and / or potassium bicarbonate and / or sodium carbonate and / or potassium carbonate; Step 1) The solvent is water, and the amount used is 10-15 mL / g inorganic alkaline reagent; Step 1) The raw material is carbocysteine, and its usage is 2.1-2.2 g / g inorganic alkaline reagent.

3. A method for preparing S-carboxymethyl-L-cysteine ​​sulfone according to claim 1 or 2, characterized in that, Step 1) The cooling treatment is to cool to -20 to -10 °C and maintain a constant temperature; Step 1) The oxidant is a hydrogen peroxide solution, the dosage of which is 0.43-0.52 mL / mL of solvent, first added dropwise at a rate of 0.25-0.35 mL / min, and then added dropwise at a rate of 0.50-0.60 mL / min; Step 1) The slow heating is to control the system to slowly heat up to 55-65°C by adding an oxidant dropwise and maintain a constant temperature; Step 1) The reaction is carried out at a constant temperature for 4 to 24 hours after the oxidant is added dropwise.

4. The method for preparing S-carboxymethyl-L-cysteine ​​sulfone according to claim 1, characterized in that: Step 2) the acid solution is hydrochloric acid and / or sulfuric acid, the concentration of which is 3-6 g / L, and the pH value of the system is adjusted to 1-2; Step 2) The low temperature treatment is to crystallize at a constant temperature of -15 to -5 °C for 24 to 30 hours, keep stirring, and control the stirring speed to be lower than 15 RPM.

5. The method for preparing S-carboxymethyl-L-cysteine ​​sulfone according to claim 1, characterized in that: Step 3) The process of adding solvent to pulp is as follows: Add 4-5 mL of water per gram of crude product, mix well, and beat for 5-10 minutes; Step 3) The solvent washing is washing the filter cake with water.

6. A method for preparing S-carboxymethyl-L-cysteine ​​sulfone according to claim 1, 4 or 5, characterized in that: The drying in step 2) and step 3) is performed by vacuum drying at 45-55°C for 1-4 hours.

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