Preparation method of S-carboxymethyl-L-cysteine sulfoxide

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of S-carboxymethyl-L-cysteine sulfoxide. The method comprises the following steps: (1) taking carbocisteine as a raw material, adding an oxidizing agent for reaction, and preparing an S-carboxymethyl-L-cysteine sulfoxide crude product through one-step reaction; and (2) pulping and purifying the S-carboxymethyl-L-cysteine sulfoxide crude product, filtering and separating solids, drying to obtain high-purity S-carboxymethyl-L-cysteine sulfoxide, and / or recovering filtrate generated in the pulping and purifying process, crystallizing the filtrate, filtering and drying to obtain the high-purity S-carboxymethyl-L-cysteine sulfoxide. The process for directly preparing S-carboxymethyl-L-cysteine sulfoxide provided by the invention is simple and efficient in process, and used chemical reagents and solvents are low in cost and easy to obtain.

Description

Technical Field

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

[0002] Carbocysteine, a commonly used expectorant in clinical practice, has a chemical name of S-(carboxymethyl)-cysteine. The drug is mainly used to treat thick sputum and difficulty in expectoration caused by diseases such as chronic bronchitis and bronchial asthma. During the production and storage process of carbocysteine, sulfoxide impurities may be generated. Sulfoxides are sulfur-containing organic compounds, and their molecular structure contains sulfur atoms and sulfoxide groups (-S(=O)-). During the synthesis and storage stages of the drug, sulfur-containing compounds are susceptible to oxidation, causing thioethers to be oxidized to sulfoxides, and even further oxidized to sulfones. As a sulfur-containing drug, carbocysteine ​​may form a sulfoxide structure under oxidative conditions, and then produce corresponding impurities, which in turn change the molecular structure and pharmacological and toxicological characteristics, and then cause harm.

[0003] After carbocysteine ​​is further oxidized to S-carboxymethyl-L-cysteine ​​sulfoxide, its hygroscopicity increases significantly, making it difficult to form a stable solid state, and the powder fluidity decreases, which is not conducive to long-term storage. During use, some products may suffer losses or pollution, resulting in waste of resources. As the sulfoxide impurity of carbocysteine, the presence of S-carboxymethyl-L-cysteine ​​sulfoxide has an important impact on drug quality control and the health and safety of users. At present, there is no public technology that can provide an amlodipine impurity that can obtain a specific appearance and morphology under a mild condition, is easy to operate, and can be obtained. To overcome the above-mentioned difficulties, the present invention proposes a method for synthesizing and separating and purifying carbocysteine ​​impurities. Summary of the invention

[0004] The technical solution of the present invention aims at the synthesis technical difficulties of the existing public technology such as extreme synthesis conditions and complex operations, and provides a synthesis method of carbocysteine ​​impurities and applications thereof.

[0005] The main purpose of the present invention is: 1. Provide a process for directly preparing S-carboxymethyl-L-cysteine ​​sulfoxide; 2. Improve the purity of the final product of the synthesis process; 3. Ensure that the preparation process is simple and efficient and can achieve one-step synthesis.

[0006] To achieve the above objectives, the present invention adopts the following technical solutions.

[0007] A method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide, The method comprises: (1) Using carbocysteine ​​as a raw material, adding an oxidant to react, and preparing a crude product of S-carboxymethyl-L-cysteine ​​sulfoxide in one step; (2) Purifying the crude S-carboxymethyl-L-cysteine ​​sulfoxide by pulping, filtering and separating the solid and drying to obtain high-purity S-carboxymethyl-L-cysteine ​​sulfoxide, and / or recovering the filtrate produced in the pulping purification process, crystallizing the filtrate and filtering and drying to obtain high-purity S-carboxymethyl-L-cysteine ​​sulfoxide.

[0008] As a preference, Before the reaction in step (1), an alkaline solution is prepared to dissolve carbocysteine ​​and the solution is kept warm in an environment at a temperature of -20 to -10°C. The alkaline solution solute is sodium bicarbonate and / or potassium bicarbonate and / or sodium carbonate and / or potassium carbonate and / or ammonia water and / or sodium hydroxide and / or potassium hydroxide.

[0009] As a preference, The oxidant in step (1) is hydrogen peroxide; The mass ratio of carbocysteine ​​to the oxidant in step (1) is 1:(1.45-1.65).

[0010] As a preference, In step (1), the temperature is controlled at -20 to -10 °C during the process of adding the oxidant, and then the temperature is slowly increased to control the temperature at 35 to 45 °C for a one-step reaction for 4 to 24 hours; After the one-step reaction in step (1) is completed, the pH is adjusted to 1 to 3.5 using hydrochloric acid and / or sulfuric acid and / or acetic acid, and the mixture is stirred at a speed of ≤15 rpm for 24 to 30 h at a temperature of -15 to -5 °C to obtain a crude S-carboxymethyl-L-cysteine ​​sulfoxide.

[0011] As a preference, Before the beating and purification in step (2), the crude S-carboxymethyl-L-cysteine ​​sulfoxide is placed at 45-55°C and vacuum dried for 2-4 hours, then ground in a mortar and vacuum dried at 50°C for 1-2 hours; The solid separated by filtration in step (2) is placed at 45-55°C and vacuum dried for 2-4 h, then ground using a mortar and vacuum dried at 50°C for 1-2 h to obtain high-purity S-carboxymethyl-L-cysteine ​​sulfoxide.

[0012] As a preference, The crystallization in step (2) is to recover the filtrate and use hydrochloric acid and / or sulfuric acid and / or acetic acid to adjust the pH to 2-3 and the temperature to -15--5°C, and stir for 48-72 hours; The drying in step (2) is performed under vacuum at 45 to 55°C for 1 to 2 hours.

[0013] The reaction path adopted by the present invention does not require the aid of a catalyst, and the oxidation target can be achieved by using only a common oxidant (hydrogen peroxide). In the process of process implementation, the difficulties and key points are mainly concentrated in two aspects: first, the precise control of the oxidation reaction temperature, which includes the adjustment of the external temperature of the system and the precise operation of the feeding method and sequence; second, the fine regulation of the crystallization conditions, involving the precise control of the crystallization pH value, temperature, stirring rate and time. The technical challenges mainly lie in: first, the precise control of the amount of oxidant, oxidation temperature and reaction time. Insufficient oxidant dosage will result in the failure of the product to be generated or contain raw material impurities; while excessive oxidant dosage will lead to over-oxidation and the generation of sulfone impurities, which are also difficult to remove, thereby affecting the purity and properties of the product; second, the fine regulation of crystallization conditions, including the precise control of crystallization pH value, temperature, stirring rate and time. Too high a pH value will lead to the presence of two carboxyl groups in the system, which will increase the solubility; too low a pH value will cause the amino groups in the system to form salts, which will also increase the solubility, so the control of the pH value is more difficult; in addition, the control of temperature, stirring speed and time will affect the formation of the crystal structure.

[0014] In the technical solution of the present invention, the core is to provide a process method for directly preparing the sulfoxide impurities of carbocysteine, and by strictly controlling the temperature conditions during the reaction process, while ensuring that the process operation is simple and efficient, it can also have extremely high product purity. Under alkaline conditions, some non-covalent bond interactions between carbocysteine ​​molecules will undergo fracture, and this process helps to improve its solubility in solution. As the acid-base neutralization reaction proceeds, the carbocysteine ​​molecule will be converted into the corresponding carboxylate form. At the same time, hydrogen bonds will be established between hydrogen peroxide and the sulfur atoms in the carbocysteine ​​molecule, and the formation of this hydrogen bond helps the activation of the carbocysteine ​​molecule. When the activated carbocysteine ​​molecule undergoes an oxidation reaction with hydrogen peroxide, its sulfur atom will undergo an electrophilic attack with the oxygen atom, thereby forming a stable SO single bond. In this process, the negative oxygen ions in the oxidation product will combine with the cations in the hydrogen peroxide, and finally generate water molecules, accompanied by the release of electrons. The generated thiol molecules will undergo a reduction reaction with the electrons released by hydrogen peroxide, so that hydrogen peroxide is reduced and thiols are formed as intermediates. Subsequently, the sulfur atom in the thiol molecule is activated by hydrogen peroxide again, and electrophilically attacks the oxygen atom to form a S(O)-O single bond. Through further dehydrogenation reduction reaction, the sulfoxide salt is finally obtained. In an acidic environment, the metal cation in the sulfoxide salt is replaced to obtain the final product S-carboxymethyl-L-cysteine ​​sulfoxide.

[0015] In the technical solution of the present invention, another core point is to influence the purity and configuration of the final product crystal by finely regulating the crystallization conditions. In order to cultivate crystals in a solution under a low temperature environment, the three crucial parameters of pH value, temperature and time during the crystal growth process must be precisely regulated. At present, the main technical difficulty faced by this process is that the crystal cultivation is difficult. In the existing technical solutions, the conventional treatment method is usually direct rotary evaporation drying. Since all substances in the system are highly soluble in water, this leads to the presence of bound water and inorganic salts in the product, which is easy to absorb moisture, making the product appear gray, which in turn causes deterioration problems and affects the stability and ease of use of the product. In the technical solution, fine regulation of the crystallization conditions involves precise control of the crystallization pH value and temperature. In the technical solution of the present invention, the solubility of the solution is reduced by lowering the solution temperature after the one-step reaction, which is conducive to the precipitation of the target sulfoxide crystals, but the solution will be oversaturated during the actual operation. Even if the solute concentration exceeds the equilibrium solubility, the solute will not precipitate. The reason for this phenomenon is the nucleation barrier. Although the concentration exceeds the normal solubility, the driving force of this concentration difference is not large enough to cross the nucleation barrier, so it is impossible to nucleate, and crystals cannot be precipitated. At the same time, the system enters the metastable zone and cannot achieve spontaneous nucleation. The present invention changes the activity of ions in the system by adjusting the crystallization pH, thereby affecting the kinetics and thermodynamic conditions of crystallization, reducing the width of the crystallization metastable zone, shortening the crystallization induction period, and improving the crystallization reaction rate, and purifying the precipitated crystals. On the other hand, controlling the appropriate crystallization temperature can effectively regulate the supersaturation of the solution, thereby affecting the crystal nucleation and growth rate, affecting the mass transfer process between the crystal and the solution, and further affecting the purity and precipitation amount of the crystal; in a high temperature environment, the thermal motion of the lattice atoms and the grain boundary atoms may destroy the formed crystal nuclei, thereby leading to grain boundary migration and reduced lattice structure stability. When the temperature is high, the thermal fluctuation effect of the lattice atoms will cause the local interface to deviate from the ideal minimal face position, forcing the grain boundary to migrate as a whole, thereby causing structural instability. In addition, high temperature will also generate additional driving force for grain boundary migration through lattice elastic anisotropy and lattice anharmonic effects, further promoting the directional migration of grain boundaries and reducing the thermodynamic stability of the crystal nucleus.

[0016] The invention is beneficial in that the process for directly preparing S-carboxymethyl-L-cysteine ​​sulfoxide provided by the invention is simple and efficient, the chemical reagents and solvents used are low in cost and easy to obtain, and the byproduct is mainly low-toxic salt water. The process does not require additional solvent treatment, the generated waste water can be recycled, and the environmental impact is reduced. After purification, a white solid product with a purity of more than 95% can be obtained. After the reaction, only acidification treatment is required, and the solvent residue is easy to remove, and the carbocysteine ​​sulfoxide solid product finally obtained is stable and convenient for storage and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Characterization data of S-carboxymethyl-L-cysteine ​​sulfoxide prepared in Example 1; Figure 2 Characterization data of S-carboxymethyl-L-cysteine ​​sulfoxide prepared in Example 2; Figure 3 Characterization data of S-carboxymethyl-L-cysteine ​​sulfoxide prepared in Example 3; Figure 4 Product characterization data obtained for Comparative Example 1; Figure 5 Product characterization data was obtained for Comparative Example 2; Figure 6 Product characterization data obtained for Comparative Example 3; Figure 7 Product characterization data obtained for Comparative Example 4; Figure 8 Product characterization data was obtained for Comparative Example 5. DETAILED DESCRIPTION

[0018] 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.

[0019] 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.

[0020] Example 1: A method for synthesizing carbocysteine ​​impurities The method comprises: (1) At a temperature of 25°C, 9.4 g of sodium bicarbonate was used to prepare an alkaline solution. Carbocysteine ​​was dissolved in the solution at a temperature of -20°C and kept warm. Carbocysteine ​​was used as a raw material, and hydrogen peroxide was added. Carbocysteine ​​and hydrogen peroxide were mixed in a mass ratio of 1:1.45. The mixture was kept warm at a temperature of 35°C for 24 h. HPLC was used to detect whether the reaction was complete. After the reaction was completed, hydrochloric acid was used to adjust the pH of the system to 3.5. After acidification, the mixture was stirred at a temperature of -15°C and a rotation speed of less than 10 rpm for 30 h.

[0021] (2) The crude crystals were dried under vacuum at 55 °C for 2 h, taken out and ground with a mortar, dried under vacuum at 50 °C for 1 h, the dried product was slurried with pure water for 5 min, filtered and dried, dried under vacuum at 55 °C for 2 h, the solid was taken out and ground with a mortar, and continued to be vacuum dried at 50 °C for 1 h to obtain some pure solid; the filtrate obtained by filtration was adjusted to pH 2.8 with hydrochloric acid, stirred at -15 °C for 72 h, filtered and dried, the solid was vacuum dried at 55 °C for 1 h, taken out and mixed with the pure solid to obtain S-carboxymethyl-L-cysteine ​​sulfoxide. The total yield was then calculated to be 21.2%, and the product was characterized. The characterization results are as follows: Figure 1 The retention time of the main peak of the analysis and characterization data was 2.187 min, the peak area was 1.381 mAU*min, the peak height was 24.147 mAU, and the HPLC purity was 100%.

[0022] Example 2: A method for synthesizing carbocysteine ​​impurities The method comprises: (1) At a temperature of 25°C, 9.4 g of sodium bicarbonate was used to prepare an alkaline solution. At a temperature of -15°C, carbocysteine ​​was dissolved and kept warm. At a temperature of 40°C, carbocysteine ​​and hydrogen peroxide were mixed in a mass ratio of 1:1.55 for reaction for 14 h. TLC was used to detect whether the reaction was complete. After the reaction was completed, sulfuric acid was used to adjust the pH of the system to 3.2. After acidification, the mixture was stirred at a temperature of -10°C and a rotation speed of less than 10 rpm for 27 h.

[0023] (2) The crude crystals were dried under vacuum at 50 °C for 2 h, taken out and ground with a mortar, dried under vacuum at 50 °C for 1.5 h, the dried product was slurried with pure water for 5 min, filtered and dried, dried under vacuum at 50 °C for 3 h, the solid was taken out and ground with a mortar, and continued to be vacuum dried at 50 °C for 1.5 h to obtain some pure solid; the filtrate obtained by filtration was adjusted to pH 2.5 with sulfuric acid, stirred at -10 °C for 60 h, filtered and dried, the solid was vacuum dried at 50 °C for 1.5 h, taken out and mixed with the pure solid to obtain S-carboxymethyl-L-cysteine ​​sulfoxide. The total yield was then calculated to be 20.6%, and the product was characterized. The characterization results are as follows: Figure 2 The retention time of the main peak of the analysis and characterization data was 2.187 min, the peak area was 10.078 mAU*min, the peak height was 177.674 mAU, and the HPLC purity was 98.92%.

[0024] Example 3: A method for synthesizing carbocysteine ​​impurities The method comprises: At 25 °C, 9.4 g of sodium bicarbonate was used to prepare an alkaline solution. At -10 °C, carbocysteine ​​was dissolved and kept warm. At 45 °C, carbocysteine ​​and hydrogen peroxide were mixed in a mass ratio of 1:1.65 for 6.5 h. TLC was used to detect whether the reaction was complete. After the system reaction was completed, hydrochloric acid was used to adjust the pH to 3.4. After acidification, the solution was stirred at -5 °C and a stirring speed of less than 10 rpm for 24 h.

[0025] The crude crystals were dried under vacuum and 45 °C for 2 h, taken out and ground with a mortar, dried under vacuum and 45 °C for 2 h, the dried product was slurried with pure water for 5 min, filtered and dried, dried under vacuum and 45 °C for 4 h, the solid was taken out and ground with a mortar, and continued to be vacuum dried at 50 °C for 2 h to obtain some pure solids; the filtrate obtained by filtration was adjusted to pH 2.6 with hydrochloric acid, stirred at -5 °C for 48 h, filtered and dried, the solid was vacuum dried at 45 °C for 2 h, taken out and mixed with the pure solid to obtain S-carboxymethyl-L-cysteine ​​sulfoxide. The total yield was then calculated to be 24.3%, and the characterization was performed. The characterization results are as follows: Figure 3 The retention time of the main peak of the analysis and characterization data was 2.183 min, the peak area was 3.357 mAU*min, the peak height was 53.937 mAU, and the HPLC purity was 96.52%.

[0026] Comparative Example 1: A method for synthesizing carbocysteine ​​impurities. The specific preparation method is the same as that of Example 2, except that the reaction temperature of the present invention is regulated to prepare S-carboxymethyl-L-cysteine ​​sulfoxide. The specific operation is as follows: A kind of synthetic method of carbocysteine ​​impurity The method comprises: (1) Prepare an alkaline solution using 9.4 g of sodium bicarbonate at 25°C, dissolve carbocysteine ​​in the solution at -15°C and keep warm, mix carbocysteine ​​and hydrogen peroxide at a mass ratio of 1:1.55 at 60°C and react for 14 h, and use HPLC to detect whether the reaction is complete.

[0027] (2) HPLC showed that the reaction was incomplete and there were two substances in the reaction solution, which were characterized. The characterization results were as follows: Figure 4As shown. According to the characterization data, the sulfone impurity of carbocysteine ​​is 13.66%, the sulfoxide is 76.67%, and the unreacted carbocysteine ​​is 5.87%, which cannot be separated and catalyzed by crystallization.

[0028] Comparative Example 2: A method for synthesizing carbocysteine ​​impurities. The specific preparation method is the same as that of Example 2, except that the reaction temperature of the present invention is regulated to prepare S-carboxymethyl-L-cysteine ​​sulfoxide. The specific operation is as follows: A kind of synthetic method of carbocysteine ​​impurity The method comprises: (1) At a temperature of 25°C, prepare an alkaline solution using 9.4 g of sodium bicarbonate. Dissolve carbocysteine ​​in the solution at a temperature of -15°C and keep warm. Mix carbocysteine ​​and hydrogen peroxide at a mass ratio of 1:1.55 at a temperature of 25°C and react for 14 h. Use HPLC to detect whether the reaction is complete.

[0029] (2) HPLC showed that the reaction was incomplete and there were two substances in the reaction solution, which were characterized. The characterization results were as follows: Figure 5 According to the analysis of the characterization data, the reaction solution mainly contained 95.55% of unreacted carbocysteine, and other non-target products were generated.

[0030] Comprehensive analysis of the characterization data results of Comparative Example 1 and Comparative Example 2 shows that if S-carboxymethyl-L-cysteine ​​sulfoxide is to be obtained, the temperature conditions during the reaction must be strictly controlled. If the temperature during the reaction is high, although no catalyst is added, the sulfur atoms of part of the sulfoxide will be further oxidized under the oxidation of hydrogen peroxide to obtain S-carboxymethyl-L-cysteine ​​sulfone, and part of the hydrogen peroxide is decomposed due to the high reaction temperature, and carboxymethylcysteine ​​that does not participate in the reaction exists; if the reaction temperature is low, the kinetic energy of the hydrogen peroxide molecules is insufficient, the frequency of intermolecular collisions is reduced, and it becomes difficult to reduce the entropy of the molecules during the reaction, resulting in a significant decrease in the reaction rate, so that the unreacted carboxymethylcysteine ​​in the final reaction solution accounts for a huge proportion.

[0031] Comparative Example 3: A method for synthesizing a carbocysteine ​​impurity. The specific preparation method is the same as that of Example 2, except that the pH conditions for precipitating crystals of the present invention are regulated to prepare S-carboxymethyl-L-cysteine ​​sulfoxide. The specific operation is as follows: A kind of synthetic method of carbocysteine ​​impurity The method comprises: (1) At a temperature of 25°C, 9.4 g of sodium bicarbonate was used to prepare an alkaline solution. At a temperature of -15°C, carbocysteine ​​was dissolved and kept warm. At a temperature of 40°C, carbocysteine ​​and hydrogen peroxide were mixed in a mass ratio of 1:1.55 for reaction for 14 h. HPLC was used to detect whether the reaction was complete. After the reaction was completed, sulfuric acid was used to adjust the pH of the system to 4.0. After acidification, the mixture was stirred at a temperature of -10°C and a rotation speed of less than 10 rpm for 27 h.

[0032] (2) There was no obvious solid precipitation in the system. When the crystallization time was extended to 72 h, no solid precipitation was observed. When the system was stirred for 60 h at a temperature of -15 °C, no solid precipitation was observed. The residual liquid was characterized. The characterization results are shown in Figure 6 As shown, according to the analysis of the characterization data, the unreacted carbocysteine ​​in the reaction solution is 0.3%, and the S-carboxymethyl-L-cysteine ​​sulfoxide component accounts for 97.59%.

[0033] Comparative Example 4: A method for synthesizing carbocysteine ​​impurities. The specific preparation method is the same as that of Example 2, except that the pH conditions for precipitating crystals of the present invention are regulated to prepare S-carboxymethyl-L-cysteine ​​sulfoxide. The specific operations are as follows: A kind of synthetic method of carbocysteine ​​impurity The method comprises: (1) At a temperature of 25°C, 9.4 g of sodium bicarbonate was used to prepare an alkaline solution. At a temperature of -15°C, carbocysteine ​​was dissolved and kept warm. At a temperature of 40°C, carbocysteine ​​and hydrogen peroxide were mixed in a mass ratio of 1:1.55 for reaction for 14 h. HPLC was used to detect whether the reaction was complete. After the reaction was completed, hydrochloric acid was used to adjust the pH of the system to 1.5. After acidification, the mixture was stirred at a temperature of -10°C and a rotation speed of less than 10 rpm for 27 h.

[0034] (2) There was no obvious solid precipitation in the system. When the crystallization time was extended to 72 h, no solid precipitation was observed. When the system was stirred for 60 h at a temperature of -15 °C, no solid precipitation was observed. The residual liquid was characterized. The characterization results are shown in Figure 7 As shown, according to the analysis of the characterization data, the unreacted carbocysteine ​​in the reaction solution accounted for 0.29%, and the S-carboxymethyl-L-cysteine ​​sulfoxide component accounted for 95.76%.

[0035] Comprehensive analysis of the characterization data results of Comparative Examples 3 and 4 shows that precise control of pH during the crystallization process can obtain sulfoxide crystals. It is observed that the reaction solutions of Comparative Examples 3 and 4 contain a large amount of S-carboxymethyl-L-cysteine ​​sulfoxide, but they cannot precipitate independently. After further research, if the pH value is too high during the crystallization process, two carboxyl groups will be generated in the system, thereby increasing the solubility; if the pH value is too low, the amino groups in the system will be salified, which will also increase the solubility. At the same time, other impurity ions, especially hydrogen ion eutectic, will precipitate, but more hydrogen bonds will appear in the crystal structure, which will not only produce new impurities, but also increase the solubility, making it difficult for crystals to precipitate.

[0036] Comparative Example 5: A method for synthesizing carbocysteine ​​impurities. The specific preparation method is the same as that of Example 2, except that the temperature conditions for crystal precipitation of the present invention are regulated to prepare S-carboxymethyl-L-cysteine ​​sulfoxide. The specific operation is as follows: A kind of synthetic method of carbocysteine ​​impurity The method comprises: (1) At a temperature of 25°C, 9.4 g of sodium bicarbonate was used to prepare an alkaline solution. At a temperature of -15°C, carbocysteine ​​was dissolved and kept warm. At a temperature of 40°C, carbocysteine ​​and hydrogen peroxide were mixed in a mass ratio of 1:1.55 for reaction for 14 h. HPLC was used to detect whether the reaction was complete. After the reaction was completed, hydrochloric acid was used to adjust the pH of the system to 3.2. After acidification, the mixture was stirred at a temperature of -20°C and a rotation speed of less than 10 rpm for 27 h.

[0037] (2) The entire system is frozen and cannot continue to crystallize. After the ice in the system melts, the liquid is characterized. The characterization results are as follows: Figure 8 As shown, according to the analysis of the characterization data, the S-carboxymethyl-L-cysteine ​​sulfoxide component accounted for 95.76%, and the unreacted carbocysteine ​​accounted for 0.81%.

[0038] Analyze the data characterization results and synthesis phenomena of Comparative Example 5. Under low temperature environment, the solubility of solute will usually decrease, which may cause the supersaturation of solute to increase during crystallization, thereby promoting the formation of crystals. However, low temperature will also slow down the diffusion rate of molecules and ions, which may hinder the growth of crystals. In addition, under given temperature conditions, the kinetic spinodal temperature of crystal growth will decrease. Below the kinetic spinodal temperature, the diffusion motion of molecules slows down and vibration weakens, resulting in a decrease in the crystal growth rate, which is unfavorable for the effective formation and growth of crystals. At the same time, the formation and growth of ice crystals may also have an adverse effect on the growth and formation of sulfoxide crystals.

Claims

1. A method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide, characterized in that: The method comprises: (1) Using carbocysteine ​​as a raw material, adding an oxidant to react, and preparing a crude product of S-carboxymethyl-L-cysteine ​​sulfoxide in one step; (2) Purifying the crude S-carboxymethyl-L-cysteine ​​sulfoxide by pulping, filtering and separating the solid and drying to obtain high-purity S-carboxymethyl-L-cysteine ​​sulfoxide, and / or recovering the filtrate produced in the pulping purification process, crystallizing the filtrate and filtering and drying to obtain high-purity S-carboxymethyl-L-cysteine ​​sulfoxide.

2. The method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide according to claim 1, characterized in that: Before the reaction in step (1), an alkaline solution is prepared to dissolve carbocysteine ​​and the solution is kept warm in an environment at a temperature of -20 to -10°C. The alkaline solution solute is sodium bicarbonate and / or potassium bicarbonate and / or sodium carbonate and / or potassium carbonate and / or ammonia water and / or sodium hydroxide and / or potassium hydroxide.

3. The method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide according to claim 1, characterized in that: The oxidant in step (1) is hydrogen peroxide; The mass ratio of carbocysteine ​​to the oxidant in step (1) is 1:(1.45-1.65).

4. The method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide according to claim 1, characterized in that: In step (1), the temperature is controlled at -20 to -10 °C during the process of adding the oxidant, and then the temperature is slowly increased to control the temperature at 35 to 45 °C for a one-step reaction for 4 to 24 hours; After the one-step reaction in step (1) is completed, the pH is adjusted to 1 to 3.5 using hydrochloric acid and / or sulfuric acid and / or acetic acid, and the mixture is stirred at a speed of ≤15 rpm for 24 to 30 h at a temperature of -15 to -5 °C to obtain a crude S-carboxymethyl-L-cysteine ​​sulfoxide.

5. The method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide according to claim 1, characterized in that: Before the beating and purification in step (2), the crude S-carboxymethyl-L-cysteine ​​sulfoxide is placed at 45-55°C and vacuum dried for 2-4 hours, then ground in a mortar and vacuum dried at 50°C for 1-2 hours; The solid separated by filtration in step (2) is placed at 45-55°C and vacuum dried for 2-4 h, then ground using a mortar and vacuum dried at 50°C for 1-2 h to obtain high-purity S-carboxymethyl-L-cysteine ​​sulfoxide.

6. The method for preparing S-carboxymethyl-L-cysteine ​​sulfoxide according to claim 1, characterized in that: The crystallization in step (2) is to recover the filtrate and use hydrochloric acid and / or sulfuric acid and / or acetic acid to adjust the pH to 2-3 and the temperature to -15--5°C, and stir for 48-72 hours; The drying in step (2) is performed under vacuum at 45 to 55°C for 1 to 2 hours.

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