Synthesis and preparation method of high-purity fudosteine and product thereof

Abstract

The invention relates to the technical field of biological pharmacy, and discloses a synthesis and preparation method of high-purity fudosteine and a product thereof, the synthesis and preparation method comprises the following steps: carrying out substitution reaction on L-cysteine and 3-chloro-1-propanol, adding ammonia water and dithiothreitol or mercaptoethanol in the reaction, adjusting the pH after the reaction is finished, then adding ethanol for crystallization, and carrying out hot pulping to obtain the high-purity fudosteine. Filtering at room temperature to obtain a high-purity fudosteine product; or dithiothreitol or mercaptoethanol is not added in the substitution reaction stage, after the substitution reaction is finished and the pH is adjusted, ethanol is used for crystallization and thermal pulping, then filtration is performed to obtain a fudosteine crude product, the crude product is dissolved in ethanol, dithiothreitol or mercaptoethanol is added for reaction, filtration is performed, and a filter cake is pulped by ethanol at room temperature and dried in vacuum to obtain a high-purity fudosteine product. The method provided by the invention is simple and convenient to operate, high in yield and low in production cost, high-risk operation links such as hot filtration are avoided, and a high-purity fudosteine product with the impurity content lower than 0.1% can be directly obtained without tedious recrystallization operation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biopharmaceutical technology, and more particularly to a synthetic preparation method of high-purity fudosteine and a product thereof. BACKGROUND

[0002] Fudosteine is a cysteine derivative with the chemical name of (2R)-2-amino-3-(3-hydroxypropylthio)propanoic acid, a molecular formula of C6H 13 NO3S, and a molecular weight of 179.24. It is jointly developed by Mitsubishi Pharmaceutical and S.S Pharmaceutical for the treatment of respiratory diseases such as bronchial asthma, chronic asthmatic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, chronic obstructive pulmonary emphysema, atypical mycobacteriosis, pneumonia, and diffuse panbronchiolitis. It was first marketed in Japan in 2001 and in China in 2009. In 2024, the Chinese Guidelines for Primary Diagnosis, Treatment and Management of Chronic Obstructive Pulmonary Disease will list fudosteine as a first-line expectorant for stable COPD patients with viscous sputum.

[0003] The synthesis of fudosteine usually takes L-cysteine as the raw material and is achieved through two main paths: one is the nucleophilic substitution reaction with 3-halo-1-propanol under alkaline conditions; the other is the free radical addition reaction initiated by potassium persulfate-sodium bisulfite redox system, ultraviolet irradiation or heat. The L-cysteine molecule has strong reducing properties and is easily oxidized under certain conditions, thereby forming L-cystine. This process is particularly significant in high-temperature, neutral or alkaline environments. According to the public information of the Japanese Pharmacopoeia and the Chinese Pharmacopoeia, there are significant differences in the quality standards of fudosteine bulk drug in terms of impurity control: the Japanese Pharmacopoeia has a relatively lenient limit on L-cystine as a specific impurity, with a limit of not higher than 2.0%, while the current Chinese standard has significantly improved the limit of L-cystine residue to not more than 0.1% through more stringent analysis methods and risk assessment. In view of the potential oxidative side reaction risk in the synthesis process of fudosteine, China has strengthened the quality control requirements of L-cysteine oxidation impurities to improve the safety of fudosteine medication.

[0004] The invention patent with publication number CN108752250A discloses a synthesis method of high-purity foudrostan. The method is to add foudrostan crude product into water at 35℃ and stir to dissolve, then add anhydrous ethanol and warm to 40℃ for 30min, filter, drop anhydrous ethanol into the filtrate, then cool to 0℃ and filter and dry to obtain foudrostan finished product. The purity of foudrostan prepared by this method can reach 99.52%, but the content of impurity L-cystine is not reported. The L-cystine impurity in the foudrostan finished product obtained by the technology is as high as 0.42%, which does not meet the quality requirements of Chinese Pharmacopoeia. After three times of recrystallization with ethanol-water, the L-cystine is reduced to 0.06%. Although the L-cystine can meet the limit requirements after multiple recrystallizations, the product loss is very serious, and the total yield after purification is only 40%. Moreover, repeated recrystallization leads to complicated process and is difficult to be large-scale industrialized production.

[0005] For another example, the invention patent with publication number CN102180820A discloses a purification method of high-purity foudrostan. The method is that the foudrostan reaction solution is first evaporated under reduced pressure, the residue is repeatedly washed with acetone and then crushed to obtain a powder; the obtained powder is treated by ion exchange chromatography and ammonia as eluent, the eluate is collected and concentrated under reduced pressure to obtain a residue which is foudrostan crude product. The foudrostan crude product is heated and dissolved in water, activated carbon is added for adsorption and decolorization, filtered, and then methanol is added to crystallize at 10℃, filtered and dried to obtain foudrostan pure product. The method only reports that the purity can reach 99.5%~99.7%, and the impurity level of L-cystine is not reported. This method uses ion exchange chromatography for primary purification, which leads to complex production process, high production cost, large equipment investment, and is not conducive to large-scale production.

[0006] In addition, the invention patent with publication number CN118324672A discloses a production process and purification method of high-purity foudrostan. The method is that cysteine hydrochloride and 3-chloro-1-propanol are heated to react after being adjusted to alkaline with NaOH, the pH is adjusted after the reaction is completed, filtered, evaporated water under reduced pressure, filtered while hot, the mother liquor is cooled to crystallize, filtered, the filter cake is washed with cold ethanol aqueous solution, and the foudrostan crude product is obtained. The crude product is added into purified water and heated to 40-60℃ to dissolve, then cooled to crystallize and filtered. The filter cake is washed with anhydrous ethanol and dried to obtain the finished product, and the cystine impurity is 0.05%~0.08%. This impurity removal method needs to evaporate water repeatedly, the operation process is very complicated and the hot filtration safety risk is high, which is not conducive to large-scale industrialized production.

[0007] The patent for invention with publication number CN114644579A discloses a preparation method of foudostatin. Hydrochloric acid cysteine and 3-chloro-1-propanol are reacted in lye to obtain a foudostatin reaction liquid. The reaction liquid is purified by electrodialysis to obtain the foudostatin crude product. The crude product is dissolved in water, and then subjected to active carbon decolorization, filtration, ethanol crystallization, ethanol beating, filtration and drying to obtain the foudostatin product, and the L-cystine content is 0.01% to 0.05%. The dialysis system used in the method has problems of high energy consumption, membrane pollution and scaling risk, large equipment investment and high operation cost in industrial application.

[0008] The above-mentioned problems of the prior art in preparing high-purity foudostatin mainly include the following: first, repeated water evaporation, hot filtration and crystallization are required, the operation process is very complicated, the hot filtration has high safety risk, and it is not conducive to large-scale industrial production; second, ion exchange chromatography or dialysis system is used for impurity removal, which has problems of complicated process, high energy consumption, large equipment investment and high operation cost in industrial application; and third, repeated recrystallization with a mixed solvent of water and alcohol can reduce the L-cystine impurity content to a certain extent, but the product loss is very serious, the purification process is complicated, the yield is low, the production cost is high, and it is difficult to be large-scale industrialized. SUMMARY

[0009] In view of the problems and deficiencies of the prior art, the present application provides a synthetic preparation method of high-purity foudostatin and the product thereof. The synthetic preparation method has the advantages of simple operation, high yield and low production cost, avoids repeated water evaporation and hot filtration, effectively overcomes the limitations of the prior art, and is particularly suitable for industrial large-scale production of foudostatin. In particular, the method can directly obtain high-purity foudostatin product with L-cystine impurity less than 0.1% without complicated recrystallization operation, and the related substances and other quality indicators fully meet the strict standard requirements of Chinese Pharmacopoeia.

[0010] In order to achieve the above-mentioned application purposes, the technical solutions of the present application are as follows: The present application discloses a synthetic preparation method of high-purity foudostatin, which is as follows: Step S1. L-cysteine and 3-chloro-1-propanol are taken as raw materials for preparing foudostatin product, and substitution reaction is carried out. Ammonia water is added as an acid-binding agent during the reaction. After the reaction is completed, a foudostatin reaction liquid is obtained. During the substitution reaction, the molar ratio of L-cysteine to 3-chloro-1-propanol is 1:1.0 to 1.2. Step S2. Acetic acid is added to the foudostatin reaction liquid after the reaction to adjust the pH to 5 to 6. Step S3. Crystallization is performed by adding an ethanol solution with a concentration of 60-85% to the fodositan reaction solution after adjusting the pH, and hot beating is performed, then after cooling to room temperature, fodositan crude product is obtained by filtration; Step S4. The prepared fodositan crude product is added to an ethanol solution with a concentration of 60-85%, heated to dissolve, then dithiothreitol or mercaptoethanol is added to the solution, after stirring for 1-5h, cooling to room temperature and filtration; Step S5. The filter cake obtained by filtration is beaten with an ethanol solution with the same concentration as step S4 at room temperature, and finally high-purity fodositan product is obtained by vacuum drying, the impurity content of the high-purity fodositan product is less than 0.1%.

[0011] Another aspect of the present application also discloses a synthetic preparation method of high-purity fodositan, which is specifically as follows: Step A. L-cysteine and 3-chloro-1-propanol are taken as raw materials for preparing fodositan product, and substitution reaction is performed thereon, ammonia is added as an acid-binding agent during the reaction, and dithiothreitol or mercaptoethanol is added to the solution at the same time; during the substitution reaction, the molar ratio of L-cysteine to 3-chloro-1-propanol is 1:1.0-1.2 Step B. After the reaction is completed, acetic acid is added to the reaction solution to adjust the pH to 5-6; Step C. Crystallization is performed by adding an ethanol solution with a concentration of 60-85% to the reaction solution after adjusting the pH, and hot beating is performed, then after cooling to room temperature, high-purity fodositan product with an impurity content of less than 0.1% is obtained by filtration.

[0012] In the above preparation method, the substitution reaction temperature between L-cysteine and 3-chloro-1-propanol is controlled at 35-45℃, and the substitution reaction time is 12-18h.

[0013] As a preferred, the amount of ammonia used in the substitution reaction is 1.2-1.4 times the molar amount of L-cysteine.

[0014] As a preferred, the hot beating temperature is 40-70℃.

[0015] As a preferred, the amount of dithiothreitol or mercaptoethanol used is 0.5%-5% of the molar amount of L-cysteine.

[0016] Based on the same inventive concept, another aspect of the present application also discloses a high-purity fodositan product, which is prepared according to the above-mentioned synthetic preparation method of high-purity fodositan, and in the prepared high-purity fodositan product, the L-cystine impurity content is less than 0.1%.

[0017] The beneficial effects of the present application are: 1. The present application adds dithiothreitol or mercaptoethanol to the crude solution of fodositan, which can convert the impurity L-cystine in the crude product into L-cysteine with good water solubility. Without going through the cumbersome recrystallization process, high-purity fodositan product with L-cystine impurity content less than 0.1% can be directly obtained, and the related substances fully meet the strict standard requirements of Chinese Pharmacopoeia.

[0018] 2. The method of the present application has the advantages of simple operation, high yield and low production cost, and avoids high-risk operation links such as heat filtration, effectively overcomes the limitations of the prior art, and is particularly suitable for industrial large-scale production of fodositan. BRIEF DESCRIPTION OF DRAWINGS

[0019] The foregoing and subsequent specific description of the present application becomes clearer when read in conjunction with the following drawings, in which: Figure 1 The HPLC spectrum of L-cystine impurity in the fodositan product of Example 1.

[0020] Figure 2 The HPLC spectrum of L-cystine impurity in the fodositan product of Example 3.

[0021] Figure 3 The HPLC spectrum of L-cystine impurity in the fodositan product of Comparative Example 1.

[0022] Figure 4 The HPLC spectrum of L-cystine impurity in the fodositan product prepared by three recrystallizations of Comparative Example 1. DETAILED DESCRIPTION

[0023] In order for those skilled in the art to better understand the technical solutions in the present application, the following will further illustrate the technical solutions for achieving the purposes of the present application through specific examples. It should be noted that the technical solutions claimed by the present application include but are not limited to the following examples. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor shall fall within the scope of protection of the present application.

[0024] The present application aims to provide a method for synthesizing high-purity fodositan, which can efficiently remove L-cystine impurities generated during preparation, and finally prepare high-purity fodositan. The L-cystine impurity content in the prepared high-purity fodositan product is less than 0.1%, which meets the quality requirements of Chinese Pharmacopoeia.

[0025] The specific embodiments of the present application will be described below in conjunction with specific examples. However, the protection scope of the present application is not limited to the following examples.

[0026] It should be noted that the following examples and comparative examples are: L-cystine impurity reference high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition Volume 4 General 0512) was determined. Chromatographic conditions: octadecylsilane bonded silica gel as the filler (Alltech Alltima C18 column, 4.6 mm x 250 mm, 5 μm or a chromatographic column with equivalent performance) was used; 0.05 mol / L phosphate buffer (take potassium dihydrogen phosphate 6.8 g, add water 1000 ml to dissolve, adjust pH to 4.0 with phosphoric acid) was used as mobile phase A; acetonitrile-water (80:20) was used as mobile phase B; gradient elution was performed according to the following table; the flow rate was 0.5 ml per minute; the column temperature was 30°C; the detection wavelength was 210 nm. The injection volume was 20 μl.

[0027] Example 1 In a 10 L glass reactor, purified water (150 mL), 3-chloro-1-propanol (85.8 g, 0.908 mol), L-cysteine (100 g, 0.825 mol) and ammonia water (337 g, 0.99 mol) were sequentially added. The liquid temperature in the reactor was controlled at 35-45°C, and the substitution reaction of 3-chloro-1-propanol and L-cysteine in the reactor occurred under the condition of ammonia water as an acid binding agent; after 14 hours of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6; then 5 L of ethanol was added to the system, and after 1 h of 45°C insulation and cooling to room temperature, the crude fondosilane was obtained by filtration.

[0028] The crude fondosilane was dissolved in 85% ethanol under reflux, then dithiothreitol (2.47 g, 0.016 mol) was added, stirred for 1 h, cooled to room temperature and filtered; the filter cake obtained after filtration was reslurried in 85% ethanol at room temperature for 1 h and then filtered again; finally, the filter cake obtained after the second filtration was dried at 60°C under vacuum to obtain high-purity fondosilane product 124 g, with L-cystine residue of 0.04% detected by HPLC, and total yield of 82.4%.

[0029] Example 2 In a 10 L glass reactor, purified water (150 mL), 3-chloro-1-propanol (85.8 g, 0.908 mol), L-cysteine (100 g, 0.825 mol) and ammonia water (337 g, 0.99 mol) were sequentially added. The liquid temperature in the reactor was controlled at 35-45°C, and the substitution reaction of 3-chloro-1-propanol and L-cysteine in the reactor occurred under the condition of ammonia water as an acid binding agent; after 14 hours of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6; then 5 L of ethanol was added to the system, and after 1 h of 45°C insulation and cooling to room temperature, the crude fondosilane was obtained by filtration.

[0030] The crude fondrostat potassium was dissolved in 75% ethanol, then mercaptoethanol (1.29 g, 0.016 mol) was added, stirred for 3 h, and then cooled to room temperature, and filtered. The filter cake obtained after filtration was slurried in 75% ethanol at room temperature for 1 h, and then filtered again. Finally, the filter cake was dried at 60°C under vacuum to obtain 126 g of finished fondrostat potassium, with an L-cystine residue of 0.04% detected by HPLC, and a total yield of 83.6%.

[0031] Example 3 In a 10 L glass reactor, purified water (130 mL), 3-chloro-1-propanol (78.0 g, 0.825 mol), L-cysteine (100 g, 0.825 mol), and ammonia water (337 g, 0.99 mol) were sequentially added. The liquid temperature in the reactor was controlled at 35-45°C, and the 3-chloro-1-propanol and L-cysteine in the reactor underwent substitution reaction in the presence of ammonia water as an acid-binding agent. After 12 h of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6. Then, 5 L of ethanol was added to the reaction liquid, which was then slurred at 45°C for 1 h, cooled to room temperature, and filtered to obtain the crude fondrostat potassium.

[0032] The crude fondrostat potassium was dissolved in 60% ethanol, then dithiothreitol (0.62 g, 0.004 mol) was added, stirred for 3 h, and then cooled to room temperature, and filtered. The filter cake obtained after filtration was slurried in 60% ethanol at room temperature for 1 h, and then filtered again. Finally, the filter cake was dried at 60°C under vacuum to obtain 116 g of finished fondrostat potassium, with an L-cystine residue of 0.07% detected by HPLC, and a total yield of 78.2%.

[0033] Example 4 In a 10 L glass reactor, purified water (130 mL), 3-chloro-1-propanol (78.0 g, 0.825 mol), L-cysteine (100 g, 0.825 mol), and ammonia water (337 g, 0.99 mol) were sequentially added. The liquid temperature in the reactor was controlled at 35-45°C, and the 3-chloro-1-propanol and L-cysteine in the reactor underwent substitution reaction in the presence of ammonia water as an acid-binding agent. After 12 h of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6. Then, 5 L of ethanol was added to the reaction liquid, which was then slurred at 45°C for 1 h, cooled to room temperature, and filtered to obtain the crude fondrostat potassium.

[0034] The crude fondrostat potassium was dissolved in 60% ethanol, then mercaptoethanol (3.2 g, 0.04 mol) was added, stirred for 1 h, and then cooled to room temperature, and filtered. The filter cake obtained after filtration was slurried in 60% ethanol at room temperature for 1 h, and then filtered again. Finally, the filter cake was dried at 60°C under vacuum to obtain 114 g of finished fondrostat potassium, with an L-cystine residue of undetected detected by HPLC, and a total yield of 77.2%.

[0035] Example 5 In a 10L glass reactor, purified water (130mL), 3-chloro-1-propanol (93.6g, 0.99mol), L-cysteine (100g, 0.825mol) and ammonia water (393g, 1.15mol) were sequentially added, the temperature of the liquid in the reactor was controlled at 35-45°C, and the substitution reaction of 3-chloro-1-propanol and L-cysteine in the reactor occurred in the presence of ammonia water as an acid binding agent; after 12 hours of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6; then 5.5L of ethanol was added to the reaction system, and the slurry was maintained at 45°C for 1h and then cooled to room temperature, and the crude furodosteine was obtained by filtration.

[0036] The crude furodosteine was dissolved in 65% ethanol by reflux, and then mercaptoethanol (0.64g, 0.008mol) was added, stirred for 1h, cooled to room temperature, and filtered; the filter cake obtained by filtration was slurried in 65% ethanol at room temperature for 1h and then filtered again; finally, the filter cake obtained by filtering again was dried at 60°C under vacuum to obtain the finished furodosteine product 116g, with L-cystine residue of 0.05% detected by HPLC, and the total yield of 78.8%.

[0037] Example 6 In a 10L glass reactor, purified water (150mL), 3-chloro-1-propanol (85.8g, 0.908mol), L-cysteine (100g, 0.825mol), dithiothreitol (0.62g, 0.004mol) and ammonia water (337g, 0.99mol) were sequentially added. The temperature of the liquid in the reactor was controlled at 35-45°C, and the substitution reaction of 3-chloro-1-propanol and L-cysteine in the reactor occurred in the presence of ammonia water as an acid binding agent; after 18 hours of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6; then 7L of ethanol was added to the system, and the slurry was maintained at 45°C for 1h and then cooled to room temperature, and the crude furodosteine was obtained by filtration.

[0038] The crude furodosteine was dissolved in 80% ethanol by reflux, stirred for 3h, cooled to room temperature, and filtered; the filter cake obtained by filtration was slurried in 80% ethanol at room temperature for 1h and then filtered again; finally, the filter cake obtained by filtering again was dried at 60°C under vacuum to obtain the finished furodosteine product 127g, with L-cystine residue of 0.02% detected by HPLC, and the total yield of 84.5%.

[0039] Example 7 In a 10L glass reactor, purified water (150mL), 3-chloro-1-propanol (85.8g, 0.908mol), L-cysteine (100g, 0.825mol), mercaptoethanol (0.31g, 0.004mol) and ammonia water (337g, 0.99mol) were sequentially added. The temperature of the liquid in the reactor was controlled at 35-45°C, and the substitution reaction of 3-chloro-1-propanol and L-cysteine in the reactor occurred in the presence of ammonia water as an acid-binding agent. After 18 hours of reaction, acetic acid was added dropwise to adjust the pH of the reaction system to 5-6. Then 7L of ethanol was added to the system, and after stirring at 45°C for 1h, the temperature was lowered to room temperature, and filtration was performed to obtain the crude furodosteine.

[0040] After the crude furodosteine was dissolved in 70% ethanol under reflux, it was stirred for 3h and then cooled to room temperature for filtration. The filter cake obtained after filtration was slurried in 70% ethanol at room temperature for 1h and then filtered again. Finally, the filter cake obtained was dried at 60°C under vacuum to obtain 122g of furodosteine product, with an L-cysteine residue of 0.05% detected by HPLC, and a total yield of 81.2%.

[0041] Comparative Example 1 Furodosteine was prepared according to the method of the patent for invention with publication number CN108752250A. Specifically, 100g of L-cysteine was added to 223mL of water, and 128g of 40% w aqueous methylamine was added and stirred. After the solution was clear, 94g of 3-chloro-1-propanol was added dropwise at room temperature, and after the addition was completed, the temperature was raised to 40°C and stirred for 3.5 hours. After the reaction was completed, glacial acetic acid was added to adjust the pH of the liquid to 5-6, and then 128g of 30% concentrated anhydrous ethanol was added and stirred at 35°C for 10min, and filtered. To the filtrate, 1200g of anhydrous ethanol was added to crystallize, cooled to 0°C and kept for 30min, suction filtered, and dried at 65°C for 8h to obtain 114g of crude furodosteine.

[0042] To 114g of crude furodosteine, 285g of purified water was added and stirred at 35°C until no obvious particles were present. Then 190g of anhydrous ethanol was added, the temperature was raised to 40°C and kept for 30min, and filtered on filter paper. To the filtrate, 1238g of anhydrous ethanol was added dropwise, cooled to 0°C and kept for 30min, suction filtered, and dried at 65°C for 8h to obtain 102g of purified furodosteine product. The L-cysteine residue was 0.42% detected by HPLC, and the product did not meet the limit requirements of the Chinese Pharmacopoeia.

[0043] Further, after recrystallization of 102g of furodosteine in 85% ethanol for two times, the L-cysteine residue in the product was 0.11% detected by HPLC, and after a third recrystallization, the L-cysteine residue was 0.06%, which met the limit requirements of the Chinese Pharmacopoeia. The product was 59g, and the total yield was 40%.

[0044] The related substance and yield statistics of the above-mentioned examples 1-7 and comparative example 1 are shown in Table 1 below.

[0045] Table 1: L-cystine and yield data of examples 1-7 and comparative example 1 Table 2: Fodostatin product inspection data of example 3 The experimental data show that the method of the present application has significant advantages in the control of L-cystine impurities: the fodostatin products prepared based on the preparation methods of examples 1 to 7 not only strictly control the content of this impurity within the limit of 0.1%, but also maintain a high yield (77.2%~84.5%), and the quality indicators of the prepared fodostatin all meet the requirements of the Chinese Pharmacopoeia. In contrast, the content of L-cystine impurity in the fodostatin prepared by comparative example 1 is as high as 0.42%, which exceeds the standard of the Pharmacopoeia; although the product obtained by comparative example 1 meets the impurity limit after three recrystallizations, the product loss is serious due to multiple recrystallizations, and the yield is greatly reduced to 40%.

[0046] Therefore, these comparative results fully prove that the method of the present application has achieved important breakthroughs in impurity control and process economy: on the one hand, it significantly improves the removal efficiency of L-cystine, and on the other hand, it greatly reduces the production cost by simplifying the process, providing a more optimal technical solution for the industrial production of fodostatin In addition, batch production is carried out by the preparation method of example 3 of the present application, with a batch size of 100 kg / batch. The fodostatin products of each batch are detected, and the detection results are shown in Table 3. The experimental data show that by using the synthesis preparation method proposed by the present application, the content of the impurity L-cystine in the fodostatin product obtained from each batch is controlled within the limit of 0.1%. Therefore, it is shown that the high-purity fodostatin synthesis preparation method proposed by the present application has high stability, and the prepared fodostatin products have high consistency.

[0047] Table 3: L-cystine and yield data of each batch The above is only a preferred embodiment of the present application, and does not limit the present application in any form. Any simple modification or equivalent change made on the basis of the technical essence of the present application to the above embodiment falls within the protection scope of the present application.

Claims

1. A method for synthesizing high-purity fudosteine, characterized in that: The synthetic preparation method is as follows: L-cysteine ​​is subjected to a substitution reaction with 3-chloro-1-propanol, and ammonia and dithiothreitol or mercaptoethanol are added during the reaction. After the reaction, acetic acid is added to the reaction solution to adjust the pH of the solution; ethanol is then added to the reaction solution for crystallization and hot slurrying, and the solution is cooled to room temperature and filtered to obtain a high-purity fudosteine ​​product with an impurity content of less than 0.1%; or L-cysteine ​​is subjected to a substitution reaction with 3-chloro-1-propanol, and ammonia water is added during the reaction. After the reaction, acetic acid is added to the reaction solution to adjust the pH of the solution; ethanol is then added to the reaction solution for crystallization and hot slurrying, and the solution is cooled to room temperature and filtered to obtain a crude fudosteine ​​product; the crude fudosteine ​​product is added to an ethanol solution and heated to dissolve, and then dithiothreitol or mercaptoethanol is added to the solution. The solution is stirred for a period of time, cooled to room temperature, and filtered; the filter cake obtained by filtration is slurried with an ethanol solution at room temperature, and finally vacuum dried to obtain a high-purity fudosteine ​​product with an impurity content of less than 0.1%; In the substitution reaction, the molar ratio of L-cysteine ​​to 3-chloro-1-propanol is 1:1.0-1.

2.

2. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: The substitution reaction temperature is controlled at 35-45° C., and the reaction time is 12-18 hours.

3. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: In the substitution reaction, the amount of ammonia water used is 1.2 to 1.4 times the molar amount of L-cysteine.

4. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: The hot beating temperature is 40-70°C.

5. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: The concentration of ethanol used in ethanol crystallization and hot beating is 60~85%.

6. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: The concentration of the ethanol solution used for dissolving the crude fudosteine ​​and beating at room temperature is 60~85%.

7. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: The amount of dithiothreitol or mercaptoethanol used is 0.5% to 5% of the molar amount of L-cysteine.

8. The method for synthesizing high-purity fudosteine ​​according to claim 1, wherein: After adding dithiothreitol or mercaptoethanol to the solution, the stirring reaction time is 1 to 5 hours.

9. A high-purity fudosteine ​​product, characterized in that: The high-purity fudosteine ​​product is prepared according to the synthetic preparation method according to any one of claims 1 to 8.

10. A high-purity fudosteine ​​product according to claim 9, characterized in that: The impurity content in the high-purity fudosteine ​​product is less than 0.1%.

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