Crystallization process of 2-methyl-4-amino-5-(thioformylthio) pyrimidine sodium salt

Abstract

The invention relates to the technical field of purification of intermediates in vitamin B1 production, in particular to a 2-methyl-4-amino-5-(thioformylthio) pyrimidine sodium salt crystallization process which comprises the following steps: mixing an aminopyrimidine aqueous solution with carbon disulfide, starting stirring and controlling the system temperature to be 28 DEG C; a sodium hydroxide solution with the mass fraction of 30% is dropwise added at the speed of 1.5 g / min, the pH value of the system is maintained to be 10.2 in the dropwise adding process, and heat preservation reaction is conducted for 1.5 h after dropwise adding is completed; by constructing a synergistic system of solvent selection, temperature control and reaction conditions, an impurity transfer path is effectively cut off, the extraction yield and purity of an intermediate are greatly improved, meanwhile, the content of key impurities is remarkably reduced, a guarantee is provided for high-quality production of downstream thiamine thiosulfate and thiamine nitrate, and compared with a traditional process, the method has the advantages that the cost is reduced, and the production efficiency is improved. And the product quality stability is greatly improved.

Description

Technical Field

[0001] This invention relates to the field of intermediate purification technology in vitamin B1 production, specifically to a crystallization process for sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine. Background Technology

[0002] As an essential nutrient for the human body, the purity, yield, and stability of the final product are directly determined by the purification quality of the intermediates used in the industrial production of vitamin B1. Sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine, a key intermediate in vitamin B1 synthesis, has always been a focus of technical expertise in the industry due to its purification process.

[0003] In existing technologies, traditional production processes often omit a dedicated crystallization and purification step, directly using the sodium salt reaction solution for downstream synthesis. This leads to the continuous transfer of impurities from the reaction system to subsequent processes, not only reducing the yield of the final product but also causing impurity content to exceed standards, affecting product quality stability. Some improved processes attempt to optimize purification effects by adjusting single parameters, such as using only low-temperature treatment or a small amount of solvent to assist crystallization, but they have failed to establish a systematic synergistic control mechanism, resulting in low intermediate extraction yields and inability to effectively separate trace impurities.

[0004] Meanwhile, existing processes are poorly adaptable to fluctuations in raw material specifications. When the content of aminopyrimidine raw materials changes, problems such as decreased reaction selectivity and increased byproducts easily arise. Furthermore, some processes suffer from low solvent utilization, poor washing effects, or unreasonable process parameter matching, which not only increases production costs but also limits the large-scale application of the process. These problems make it difficult for existing purification processes to simultaneously achieve yield, purity, economy, and industrial adaptability, necessitating the development of a highly efficient, stable crystallization purification process that meets the needs of industrial production. Summary of the Invention

[0005] The primary objective of this invention is to provide a crystallization process for sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine.

[0006] A further objective of this invention is to provide a crystallization process for sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine, comprising the following steps: (1) Sodium salt preparation: Mix aminopyrimidine aqueous solution with carbon disulfide, start stirring and control the system temperature at 28℃; add 30% sodium hydroxide solution at a rate of 1.5 g / min, maintain the pH of the system at 10.2 during the addition, and keep the reaction at the temperature for 1.5 h after the addition is completed; (2) Crystallization control: Add anhydrous ethanol to the system obtained in step (1) and stir continuously for 30 min; cool the system temperature to -5℃ at a cooling rate of 2℃ / h, and then age it at a constant temperature for 2 h after reaching the target temperature; (3) Solid-liquid separation: The crystallization system was filtered by Buchner funnel to obtain sodium salt filter cake; the filter cake was washed twice with anhydrous ethanol, and the filter was continued for 10 min after each washing to obtain sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine crystals.

[0007] Preferably, the mass of anhydrous ethanol added in step (2) is 700 parts by mass.

[0008] Preferably, the pH of the system is maintained at 10.8 during the addition of sodium hydroxide solution in step (1).

[0009] Preferably, in step (1), the sodium hydroxide solution is added at a rate of 1.0 g / min, and the reaction time after the addition is completed is 2.0 h.

[0010] Preferably, the sodium salt filter cake washed in step (3) needs to be vacuum dried: the filter cake is transferred to a vacuum drying oven and dried for 1 hour at 30°C and 0.09 MPa.

[0011] Preferably, the solvent added in step (2) is replaced with an ethanol-isopropanol mixed solvent, and the washing solvent in step (3) is also replaced with the ethanol-isopropanol mixed solvent; the mass ratio of ethanol to isopropanol in the ethanol-isopropanol mixed solvent is 4:1.

[0012] Preferably, in step (1), the mass fraction of aminopyrimidine in the aqueous solution is 18%-25%, and the amount of carbon disulfide used matches the molar amount of the aminopyrimidine.

[0013] Preferably, the target temperature of the system after cooling in step (2) is -8°C to -5°C.

[0014] Preferably, the anhydrous ethanol is used to wash the filter cake 3 times in step (3), and the mass ratio of anhydrous ethanol to filter cake is 7:11-7:12 for each wash.

[0015] Preferably, the solvent recovery step is also included: the mother liquor generated after crystallization regulation in step (2) is distilled under normal pressure, and the fraction at 78°C to 82°C is collected to complete the solvent recovery.

[0016] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention effectively cuts off the impurity transmission path by constructing a synergistic system of solvent selection, temperature control and reaction conditions, which significantly improves the extraction yield and purity of intermediates, while significantly reducing the content of key impurities. This provides a guarantee for the high-quality production of downstream thioamines and thioamine nitrates. Compared with traditional processes, the product quality stability is greatly improved.

[0017] 2. The process of this invention has strong industrial adaptability, can be compatible with aminopyrimidine raw materials with different content ranges, and maintains stable performance within a wide crystallization temperature range. It can cope with practical problems such as raw material specification fluctuations and fine-tuning of operating conditions in industrial production, and reduce the difficulty and risk of control in the production process.

[0018] 3. By optimizing the solvent ratio, washing process and drying steps, the process improves the solvent recovery rate while ensuring the purification effect. Some embodiments use mixed solvents to further reduce production costs. Moreover, the process is simple to operate and does not require investment in complex equipment, which meets the high efficiency and economic needs of industrial production.

[0019] 4. By precisely controlling reaction parameters such as pH value and dropping rate, this invention reduces the occurrence of side reactions, further improves the selectivity and reliability of the process, and the final product can maintain a low impurity growth rate even after long-term storage, significantly enhancing the market competitiveness of vitamin B1 products, and has important technical value and application prospects. Detailed Implementation

[0020] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example

[0021] (1) Sodium salt preparation: Add 340 g of aminopyrimidine aqueous solution to a 500 mL four-necked flask, wherein the mass fraction of aminopyrimidine is 21%; then add 43 g of carbon disulfide, start the stirring device, and control the system temperature at 28 °C; add 65 g of sodium hydroxide solution with a mass fraction of 30% at a rate of 1.5 g / min, and maintain the pH value of the system at 10.2 through a pH online monitoring device during the addition process; after the addition is completed, keep the reaction at the temperature for 1.5 h.

[0022] (2) Crystallization control: Add 500 g of anhydrous ethanol to a four-necked flask and stir continuously for 30 min; cool the system temperature to -5 °C at a cooling rate of 2 °C / h, and then age it at a constant temperature for 2 h after reaching the target temperature.

[0023] (3) Solid-liquid separation: The crystallization system was filtered using a Buchner funnel to obtain a filter cake of sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine. The filter cake was washed twice with 50 g of anhydrous ethanol, and the filter was filtered for 10 min after each wash to finally obtain 118.5 g of sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine crystals.

[0024] (4) Downstream application: The above sodium salt crystals were mixed and dissolved with 170 g of deionized water, and 440 g of γ-chloro-γ-acetylated alcohol was added, wherein the mass fraction of γ-chloro-γ-acetylated alcohol was 17%; the system temperature was controlled at 32℃ and the reaction was maintained for 4 h; after the reaction was completed, the system temperature was cooled to 28℃, filtered and the filter cake was washed 3 times with tap water to obtain crude thiothioamine. 100 g of dilute hydrochloric acid with a mass fraction of 25% and 200 g of deionized water were added to the crude thiothioamine, and the mixed system was heated to 85℃ and the cyclization reaction was carried out for 2 h; the system was neutralized with sodium hydroxide solution with a mass fraction of 30% to a pH value of 7.6, filtered and the filter cake was washed with tap water until neutral to obtain 147.0 g of refined thiothioamine; the finished thiothioamine nitrate was then prepared according to the conventional oxidation and neutralization process. Example

[0025] This embodiment focuses on optimizing the effect of solvent dosage on sodium salt purity in Example 1. Except for solvent dosage, all other process parameters are completely consistent with Example 1, ensuring that the variable is singular and controllable. (1) Sodium salt preparation: consistent with Example 1, i.e., add 340 g of aminopyrimidine aqueous solution (aminopyrimidine mass fraction 21%) and 43 g of carbon disulfide, control the system temperature at 28℃, add liquid alkali at a rate of 1.5 g / min, maintain the system pH at 10.2, and keep the reaction at the temperature for 1.5 h.

[0026] (2) Crystallization control: Add 700 g of anhydrous ethanol to a four-necked flask, which is 200 g more than the amount of anhydrous ethanol used in Example 1; stir continuously for 30 min; cool the system temperature to -5 °C at a cooling rate of 2 °C / h, and then age at a constant temperature for 2 h after reaching the target temperature.

[0027] (3) Solid-liquid separation: The sodium salt filter cake was obtained by vacuum filtration using a Buchner funnel; the filter cake was washed 3 times with 70 g of anhydrous ethanol, which is 1 more washing time than in Example 1. After each washing, the filter cake was vacuum filtered for 10 min to obtain 118.8 g of sodium salt crystals.

[0028] (4) Downstream application: consistent with Example 1, i.e., add 170 g of deionized water and 440 g of γ-chloro-γ-acetylacetonol (mass fraction 17%), control the system temperature at 32°C, cyclization reaction temperature at 85°C, neutralize the pH value to 7.6, and finally obtain 147.5 g of thiothioamine. Example

[0029] This embodiment focuses on optimizing the effect of system pH on reaction selectivity in Example 1. Except for the system pH, all other process parameters are completely consistent with those in Example 1: (1) Sodium salt preparation: Add 340 g of aminopyrimidine aqueous solution (21% by mass) and 43 g of carbon disulfide to a four-necked flask, start the stirring device, and control the system temperature at 28°C; add 65 g of sodium hydroxide solution with a mass fraction of 30% dropwise at a rate of 1.5 g / min, and maintain the pH value of the system at 10.8 by pH online monitoring device during the dropwise addition, which is 0.6 higher than the pH value of Example 1; after the dropwise addition is completed, keep the reaction at the temperature for 1.5 h.

[0030] (2) Crystallization control: consistent with Example 1, i.e., add 500 g of anhydrous ethanol, stir for 30 min, cool to -5 °C at a cooling rate of 2 °C / h, and age at a constant temperature for 2 h.

[0031] (3) Solid-liquid separation: consistent with Example 1, i.e., the filter cake was washed twice with 50g of anhydrous ethanol to obtain 118.6g of sodium salt crystals.

[0032] (4) Downstream application: consistent with Example 1, 147.2 grams of high-quality thiothioamine were finally obtained. Example

[0033] This embodiment focuses on optimizing the effect of the liquid alkali dropping rate on the side reactions in Example 3. The liquid alkali dropping rate is adjusted and matched with the corresponding heat preservation reaction time. All other process parameters are completely consistent with Example 3. (1) Sodium salt preparation: 340 g of aminopyrimidine aqueous solution (21% by mass) and 43 g of carbon disulfide were added to a four-necked flask, and the system temperature was controlled at 28°C. 65 g of sodium hydroxide solution with a mass fraction of 30% was added dropwise at a rate of 1.0 g / min, which was 0.5 g / min slower than that in Example 3. The pH value of the system was maintained at 10.8 during the dropwise addition. After the dropwise addition was completed, the reaction was kept at the temperature for 2.0 h, which was 0.5 h longer than that in Example 3.

[0034] (2) Crystallization control: consistent with Example 3, i.e., add 500g of anhydrous ethanol, stir for 30min, cool to -5℃, and age for 2h.

[0035] (3) Solid-liquid separation: consistent with Example 3, 118.9 grams of sodium salt crystals were obtained.

[0036] (4) Downstream application: consistent with Example 3, 147.6 grams of high-quality thiothioamine were finally obtained. Example

[0037] This embodiment focuses on optimizing the effect of residual solvent in the filter cake on the downstream reaction in Example 2, by adding a vacuum drying step. All other process parameters remain identical to those in Example 2. (1) Sodium salt preparation and crystallization control: consistent with Example 2, i.e., add 340 g of aminopyrimidine aqueous solution (mass fraction 21%), 43 g of carbon disulfide, system temperature 28℃, dropping rate 1.5 g / min, pH value 10.2, keep warm for 1.5 h, add 700 g of anhydrous ethanol, cool to -5℃, and age for 2 h.

[0038] (2) Solid-liquid separation and drying: Sodium salt filter cake was obtained by vacuum filtration using a Buchner funnel; the filter cake was washed three times with 70 g of anhydrous ethanol; the washed filter cake was transferred to a vacuum drying oven and dried for 1 h at 30 °C and 0.09 MPa vacuum to obtain 118.7 g of sodium salt crystals. The moisture content of the sodium salt crystals after drying was found to be 0.4%.

[0039] (3) Downstream application: consistent with Example 2, 147.7 grams of high-quality thiothioamine were finally obtained. Example

[0040] This embodiment addresses the issue of high cost of a single solvent in Example 2 by using an ethanol-isopropanol mixed solvent, while the remaining process parameters are completely consistent with those in Example 2. (1) Sodium salt preparation: consistent with Example 2, i.e., add 340 g of aminopyrimidine aqueous solution (mass fraction 21%), 43 g of carbon disulfide, system temperature 28℃, dropping rate 1.5 g / min, pH value 10.2, and keep warm for 1.5 h.

[0041] (2) Crystallization control: Add 700 g of mixed solvent to a four-necked flask. The mass ratio of ethanol to isopropanol in the mixed solvent is 4:1. Stir continuously for 30 min. Cool to -5 °C at a cooling rate of 2 °C / h and age at a constant temperature for 2 h.

[0042] (3) Solid-liquid separation: The sodium salt filter cake was obtained by vacuum filtration using a Buchner funnel; the filter cake was washed three times with 70 g of the above-mentioned mixed solvent of ethanol-isopropanol in a mass ratio of 4:1 to obtain 119.0 g of sodium salt crystals.

[0043] (4) Downstream application: consistent with Example 2, 147.8 grams of high-quality thiothioamine were finally obtained. Example

[0044] This embodiment expands the low content range of aminopyrimidine aqueous solution to verify the process's adaptability to fluctuations in raw material content. The remaining process parameters are the same as in Example 1. (1) Sodium salt preparation: Add 360 g of aminopyrimidine aqueous solution to a four-necked flask, wherein the mass fraction of aminopyrimidine is 18%; add 41 g of carbon disulfide, the amount of which matches the molar amount of 18% aminopyrimidine; start the stirring device and control the system temperature at 28℃; add 63 g of 30% sodium hydroxide solution at a rate of 1.5 g / min, and maintain the pH value of the system at 10.2; after the addition is completed, keep the reaction at the temperature for 1.5 h.

[0045] (2) Crystallization control: consistent with Example 1, i.e., add 500g of anhydrous ethanol, stir for 30min, cool to -5℃, and age for 2h.

[0046] (3) Solid-liquid separation: consistent with Example 1, 117.2 grams of sodium salt crystals were obtained.

[0047] (4) Downstream application: consistent with Example 1, 145.8 grams of high-quality thiothioamine were finally obtained. Example

[0048] This embodiment expands the high content range of aminopyrimidine aqueous solution to further verify the process's adaptability to raw material fluctuations. The remaining process parameters are the same as in Example 1. (1) Sodium salt preparation: Add 320 g of aminopyrimidine aqueous solution to a four-necked flask, wherein the mass fraction of aminopyrimidine is 25%; add 45 g of carbon disulfide, the amount of which matches the molar amount of 25% aminopyrimidine; start the stirring device and control the system temperature at 28℃; add 67 g of 30% sodium hydroxide solution at a rate of 1.5 g / min, and maintain the pH value of the system at 10.2; after the addition is completed, keep the reaction at the temperature for 1.5 h.

[0049] (2) Crystallization control: consistent with Example 1, i.e., add 500g of anhydrous ethanol, stir for 30min, cool to -5℃, and age for 2h.

[0050] (3) Solid-liquid separation: consistent with Example 1, 119.5 grams of sodium salt crystals were obtained.

[0051] (4) Downstream application: consistent with Example 1, 148.2 grams of high-quality thiothioamine were finally obtained. Example

[0052] This embodiment extends the low-temperature range of crystallization temperature to verify the process adaptability in the low-temperature range. The remaining process parameters are the same as in Example 1. (1) Sodium salt preparation: consistent with Example 1, i.e., add 340 g of aminopyrimidine aqueous solution (mass fraction 21%), 43 g of carbon disulfide, system temperature 28℃, dropping rate 1.5 g / min, pH value 10.2, and keep warm for 1.5 h.

[0053] (2) Crystallization control: Add 500 g of anhydrous ethanol to a four-necked flask and stir for 30 min; cool the system temperature to -8 °C at a cooling rate of 2 °C / h, which is 3 °C lower than the crystallization temperature in Example 1; after reaching the target temperature, age at a constant temperature for 2 h.

[0054] (3) Solid-liquid separation: consistent with Example 1, 119.2 grams of sodium salt crystals were obtained.

[0055] (4) Downstream application: Consistent with Example 1, 147.3 grams of refined thiothioamine were finally obtained. Comparative Example 1: (1) Sodium salt preparation: consistent with Example 1, i.e., add 340 g of aminopyrimidine aqueous solution (mass fraction 21%), 43 g of carbon disulfide, system temperature 28℃, dropping rate 1.5 g / min, pH value 10.2, and keep warm for 1.5 h.

[0056] (2) Direct downstream reaction: Without crystallization extraction, 440 g of γ-chloro-γ-acetylacetonol (17% by mass) was directly added to the sodium salt solution; the subsequent cyclization reaction and neutralization steps were consistent with those in Example 1, and finally 138.2 g of thiothioamine was obtained.

[0057] Comparative Example 2: (1) Sodium salt preparation: consistent with Example 1.

[0058] (2) Single low-temperature crystallization: without adding any solvent, the system temperature was directly cooled to -5℃ at a cooling rate of 2℃ / h and aged at a constant temperature for 2h; the filter cake was washed twice with tap water using a Buchner funnel to obtain 60.2g of sodium salt crystals.

[0059] (3) Downstream application: consistent with Example 1, 140.5 grams of high-quality thiothioamine were finally obtained.

[0060] Comparative Example 3: (1) Sodium salt preparation: consistent with Example 1.

[0061] (2) Low solvent crystallization: only 200 g of anhydrous ethanol was added to the sodium salt solution, which is 40% of the amount of anhydrous ethanol used in Example 1; the subsequent crystallization and aging steps were the same as in Example 1; after filtration, the filter cake was washed twice with 30 g of anhydrous ethanol to obtain 92.5 g of sodium salt crystals.

[0062] (3) Downstream application: consistent with Example 1, 143.8 grams of high-quality thiothioamine were finally obtained.

[0063] Comparative Example 4: (1) Sodium salt preparation: consistent with Example 1.

[0064] (2) High temperature crystallization: Add 500 g of anhydrous ethanol to the sodium salt solution; cool the system temperature to 5°C at a cooling rate of 2°C / h, which is 10°C higher than the crystallization temperature in Example 1; age at a constant temperature for 2 h; after filtration, wash the filter cake twice with 50 g of anhydrous ethanol to obtain 88.7 g of sodium salt crystals.

[0065] (3) Downstream application: consistent with Example 1, 142.6 grams of high-quality thiothioamine were finally obtained.

[0066] Comparative Example 5: (1) Sodium salt preparation: consistent with Example 1.

[0067] (2) Error co-processing: Add 500 g of anhydrous ethanol to the sodium salt solution; raise the temperature of the system to 30°C instead of cooling it, and stir for 2 h; after filtration, wash the filter cake twice with 50 g of anhydrous ethanol to obtain 35.1 g of sodium salt crystals.

[0068] (3) Downstream application: consistent with Example 1, 139.1 grams of high-quality thiothioamine were finally obtained.

[0069] Performance testing and results analysis: Test method: (1) Sodium salt extraction yield: calculated as (actual sodium salt crystal mass / theoretical sodium salt mass) × 100%, where the theoretical mass is derived from the amount of aminopyrimidine used and the reaction equation, and the molar ratio of aminopyrimidine to sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine is 1:1.

[0070] (2) Sodium salt purity: determined by high performance liquid chromatography. The chromatographic column was a C18 column with a diameter of 250 mm × 4.6 mm. The mobile phase was a methanol-water mixture with a volume ratio of 30:70. The column temperature was controlled at 30℃. The detection wavelength was 270 nm. The injection volume was 10 μL. The external standard method was used for quantification.

[0071] (3) Yield of refined thiosulfate: calculated as (actual mass of refined thiosulfate / theoretical mass of thiosulfate) × 100%. The theoretical mass is derived from the amount of aminopyrimidine used. The molar ratio of aminopyrimidine to thiosulfate is 1:1.

[0072] (4) Impurity D content: The above high performance liquid chromatography method was used to determine the content of impurity D standard. The concentration of impurity D standard was 0.1 mg / mL. The content was calculated by peak area normalization method and the detection limit was 0.001%.

[0073] (5) Stability of thiamine nitrate: The finished thiamine nitrate was stored in a constant temperature and humidity chamber at 25°C and 60% relative humidity for 3 months. Samples were taken once a month, and the impurity D content was determined by the above-mentioned high performance liquid chromatography method.

[0074] (6) Solvent recovery rate: The mother liquor generated in the crystallization process is subjected to atmospheric distillation to collect the fraction from 78°C to 82°C. The solvent recovery rate is calculated as (mass of recovered solvent / mass of added solvent) × 100%.

[0075] The test results are shown in Table 1 below: Serial Number Sodium salt extraction yield (%) Sodium salt purity (%) Yield of refined thiothioamine (%) Impurities D (%) in high-quality thioamine Impurities D (%) in thiamine nitrate finished product Impurities D (%) after 3 months of storage Solvent recovery rate (%) Example 1 97.1 98.8 95.1 0.13 0.01 0.02 85.2 Example 2 97.3 99.0 95.6 0.09 Not detected 0.01 86.5 Example 3 96.8 99.1 95.3 0.10 Not detected 0.01 85.5 Example 4 97.0 99.2 95.5 0.09 Not detected 0.01 85.8 Example 5 97.4 99.4 95.7 0.07 Not detected 0.01 86.2 Example 6 97.5 99.3 95.8 0.08 Not detected 0.01 88.1 Example 7 96.9 98.9 95.2 0.12 0.01 0.02 85.3 Example 8 97.2 99.0 95.9 0.11 0.01 0.02 85.4 Example 9 97.6 99.1 95.4 0.10 Not detected 0.01 85.6 Comparative Example 1 - - 90.5 0.50 0.27 0.35 - Comparative Example 2 49.2 95.2 91.2 0.32 0.15 0.20 - Comparative Example 3 75.3 96.5 92.8 0.28 0.12 0.18 84.9 Comparative Example 4 68.7 95.8 92.1 0.30 0.14 0.19 85.1 Comparative Example 5 28.6 94.3 90.8 0.35 0.16 0.22 84.7 The results can be analyzed as follows from Table 1 above: (1) The sodium salt extraction yields of Examples 1 to 9 were consistently between 96.8% and 97.6%, and the refined thiosulfate yields were consistently between 95.1% and 95.9%. The impurity D content gradually decreased and all met the quality requirements. Among them, Examples 7 and 8 covered the aminopyrimidine content range of 18% to 25%, and Example 9 covered the crystallization temperature range of -10℃ to 0℃, proving that the process parameters of the present invention are reasonable and have good adaptability to fluctuations in raw material content and temperature adjustments, and can cover common operating conditions in industrial production.

[0076] (2) Comparative Example 1 uses a conventional process without a crystallization step, and its refined thiothiamine yield is only 90.5%, with an impurity D content as high as 0.50%; while Example 1 shows a refined yield increase of 4.6 percentage points and an impurity D content decrease of 74%. This comparative result shows that the sodium salt crystallization extraction process added in this invention can cut off the impurity transmission path from the source, which is the core of achieving a dual improvement in yield and purity, and is significantly better than the conventional process in the prior art.

[0077] (3) Comparative Examples 2 to 5 are simple improvements or incorrect combinations of existing technologies, and their sodium salt extraction yield is only 75.3% at most, which is far lower than the 96.8% or more of the Example; and the impurity D content in the thiothioamine product is the lowest at 0.28%, which is higher than the 0.07% of the Example. For example, Comparative Example 2 only uses low temperature crystallization and no solvent, and the sodium salt extraction yield is only 49.2%; Comparative Example 5 uses an incorrect combination of solvent and high temperature, and the sodium salt extraction yield is only 28.6%; while the present invention, through the synergistic control of solvent, low temperature and pH-dropping rate, makes the sodium salt extraction yield jump to more than 97%.

[0078] (4) In Example 6, an ethanol-isopropanol mixed solvent was used, achieving a solvent recovery rate of 88.1%, which is higher than that of a single ethanol solvent, effectively reducing production costs. In Example 5, a vacuum drying step was used to increase the purity of the sodium salt to 99.4%, further reducing the risk of impurities in downstream processes. The above results demonstrate that the process of the present invention not only achieves the yield and purity targets, but also possesses good economic efficiency and practicality, meeting the needs of industrial production.

[0079] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention.

Claims

1. A crystallization process for sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine, characterized in that, Includes the following steps: (1) Sodium salt preparation: Mix aminopyrimidine aqueous solution with carbon disulfide, start stirring and control the system temperature at 28℃; add 30% sodium hydroxide solution at a rate of 1.5 g / min, maintain the pH of the system at 10.2 during the addition, and keep the reaction at the temperature for 1.5 h after the addition is completed; (2) Crystallization control: Add anhydrous ethanol to the system obtained in step (1) and stir continuously for 30 min; cool the system temperature to -5℃ at a cooling rate of 2℃ / h, and then age it at a constant temperature for 2 h after reaching the target temperature; (3) Solid-liquid separation: The crystallization system was filtered by Buchner funnel to obtain sodium salt filter cake; the filter cake was washed twice with anhydrous ethanol, and the filter was continued for 10 min after each washing to obtain sodium 2-methyl-4-amino-5-(thioformylthio)pyrimidine crystals.

2. The crystallization process according to claim 1, characterized in that, The mass of anhydrous ethanol added in step (2) is 700 parts by mass.

3. The crystallization process according to claim 1, characterized in that, In step (1), the pH of the system is maintained at 10.8 during the addition of sodium hydroxide solution.

4. The crystallization process according to claim 3, characterized in that, In step (1), the sodium hydroxide solution was added at a rate of 1.0 g / min, and the reaction time was kept warm for 2.0 h after the addition was completed.

5. The crystallization process according to any one of claims 1-4, characterized in that, The sodium salt filter cake washed in step (3) also needs to be vacuum dried: transfer the filter cake to a vacuum drying oven and dry it for 1 hour at 30°C and 0.09 MPa.

6. The crystallization process according to any one of claims 1-5, characterized in that, The solvent added in step (2) is replaced with an ethanol-isopropanol mixed solvent, and the solvent used for washing in step (3) is also replaced with the ethanol-isopropanol mixed solvent; the mass ratio of ethanol to isopropanol in the ethanol-isopropanol mixed solvent is 4:

1.

7. The crystallization process according to any one of claims 1-6, characterized in that, In step (1), the mass fraction of aminopyrimidine in the aqueous solution is 18%-25%, and the amount of carbon disulfide used matches the molar amount of the aminopyrimidine.

8. The crystallization process according to any one of claims 1-7, characterized in that, The target temperature of the system after cooling in step (2) is -8℃ to -5℃.

9. The crystallization process according to any one of claims 1-8, characterized in that, In step (3), the anhydrous ethanol is used to wash the filter cake 3 times, and the mass ratio of anhydrous ethanol to filter cake is 7:11-7:12 for each wash.

10. The crystallization process according to any one of claims 1-9, characterized in that, It also includes a solvent recovery step: the mother liquor generated after crystallization regulation in step (2) is distilled at atmospheric pressure, and the fraction at 78°C to 82°C is collected to complete the solvent recovery.