Industrial preparation method of tipiracil hydrochloride

Abstract

The invention provides an industrial preparation method of tipiracil hydrochloride, which comprises the following steps: A) reacting 5-chloro-6-chloromethyl uracil and 2-aminopyrrolidine hydrochloride in the presence of a solvent and a sodium ethoxide catalyst to obtain a reaction solution; b) controlling the temperature of the reaction liquid to be 0-10 DEG C, adding an acidic medium, adjusting the pH value of the reaction liquid to be 6.0-8.0, adding ethyl acetate, stirring and filtering; c) adding an acidic medium into the filtrate obtained in the step B) to adjust the pH value to 2.0-6.0, and stirring and filtering at 10-30 DEG C to obtain tipiracil hydrochloride; the acid medium in the step B) and the step C) is independently selected from one or more of hydrochloric acid methanol, hydrochloric acid ethanol and concentrated hydrochloric acid. According to the method disclosed by the invention, the product quality is ensured, impurities are not increased, the product purity is 99.95% or above, the operation is simple, the energy consumption is low, the solvent is low in toxicity, harmless, green and environment-friendly, and the yield can be doubled.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to an industrial preparation method for ticipiridin hydrochloride. Background Technology

[0002] The preparation method of tipiracil hydrochloride was first disclosed by Taiho (a subsidiary of Taiho Pharmaceutical Co., Ltd. of Japan) in WO9630346 and EP0763529A1, EP0884051A1, and US5744475A. The synthetic route is as follows:

[0003] .

[0004] Shingo Yano et al. reported a new method for preparing tipyrimidine hydrochloride in their paper "Bioorganic & Medicinal Chemistry, 12(2004): 3443–3450". The method uses 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride as starting materials, and synthesizes tipyrimidine hydrochloride via 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) catalysis. The route is as follows:

[0005]

[0006] Starting with 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride, tepyrimidine hydrochloride was synthesized under reflux conditions via 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) catalysis. The large amount of DBU used makes it difficult to handle and poses a significant risk of residue in the product, which is not conducive to industrial production.

[0007] Douglas and Sally Freeman et al. reported in Bioorganic & Medicinal Chemistry Letters 14 (2004) 5247–5250 that the synthetic route used 5-chloro-6-methylpyrimidine as the starting material. First, the methyl group was chlorinated using NCS, followed by condensation with 2-aminopyrrolidine hydrochloride to obtain the product. The synthetic route is as follows:

[0008]

[0009] The synthetic route results in a low overall yield of the compound, which greatly increases the preparation cost and is not conducive to industrial production.

[0010] Based on the existing processes, the main bases used in the reaction of 5-chloro-6-chloromethyluracil with diaminopyrrolidine hydrochloride are sodium ethoxide and DBU. However, the yield of sodium ethoxide as a base is low, with the highest yield of tipirimidine being only 38%. The yield of the DBU method is close to 70%, but DBU is used in large quantities and is more expensive than sodium ethoxide. Moreover, DBU is an organic base, which may leave residues in the finished product and may also introduce genotoxic impurities. Summary of the Invention

[0011] The purpose of this invention is to provide an industrial preparation method for ticipiridin hydrochloride. The method of this invention does not require secondary salt formation, avoids the introduction of DBU impurities, and doubles the yield by using the sodium ethoxide process. It also avoids risks such as difficult filtration and increased impurities, and reduces the generation of a large amount of waste liquid. This makes the operation of ticipiridin hydrochloride raw material simpler, the yield higher, and the production cost lower, making it more suitable for industrial production.

[0012] This invention discloses an industrial preparation method for tipilimidine hydrochloride, comprising the following steps:

[0013] A) 5-Chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride were reacted in a solvent and with sodium ethoxide as a catalyst to obtain a reaction solution;

[0014] B) Control the temperature of the reaction solution at 0~10℃, add acidic medium, adjust the pH of the reaction solution to 6.0~8.0, add ethyl acetate, stir, and then filter to remove inorganic salts;

[0015] C) Add an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0~4.5, stir and filter at 10~30℃ to obtain tepiramycin hydrochloride;

[0016] The acidic media in steps B) and C) are independently selected from one or more of the following: hydrochloric acid methanol, hydrochloric acid ethanol, and concentrated hydrochloric acid.

[0017] Preferably, the stirring time in step B) is 0.5 to 3 hours.

[0018] Preferably, in step B), the pH is adjusted to 6.5~7.5.

[0019] Preferably, step B) specifically comprises:

[0020] The reaction solution temperature was controlled at 0~10℃. An acidic medium was added to adjust the pH of the reaction solution to 7.0±0.2. Ethyl acetate was added, and the mixture was stirred for 1~2 hours before filtration.

[0021] Preferably, the stirring time in step C) is 2 to 6 hours.

[0022] Preferably, in step C), the pH value is adjusted to 2.0~4.0.

[0023] Preferably, step C) specifically comprises:

[0024] Add an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0~4.0, stir at 10~30℃ for 3~5 hours, and filter to obtain tepiramycin hydrochloride;

[0025] Preferably, the solid obtained by filtration in step C) is washed with ethanol and then dried to obtain tepiramycin hydrochloride.

[0026] Preferably, the drying temperature is 50~80℃ and the drying time is 6~8 hours.

[0027] Preferably, the reaction temperature in step A) is 10~30℃ and the reaction time is 10~12 hours.

[0028] This invention provides an industrial preparation method for tepiramycin hydrochloride, comprising the following steps: A) reacting 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride in a solvent and under sodium ethoxide catalyst conditions to obtain a reaction solution; B) controlling the temperature of the reaction solution at 0~10℃, adding an acidic medium to adjust the pH of the reaction solution to 6.0~8.0, adding ethyl acetate, stirring, and filtering; C) adding an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0~6.0, stirring and filtering at 10~30℃ to obtain tepiramycin hydrochloride; wherein the acidic medium in steps B) and C) is independently selected from one or more of methanol hydrochloride, ethanol hydrochloride, and concentrated hydrochloric acid. This invention addresses the current challenges of low yield, difficult processing, and unstable industrial-scale impurity control in the preparation of 5-chloro-6-chloromethyluracil and diaminopyrrolidine hydrochloride using sodium ethoxide as a base. To improve industrial-scale production, the invention employs a stepwise pH adjustment method with hydrochloric acid and methanol for the intermediate ticipiridin, removing sodium chloride inorganic salts during this process. This ensures product quality without increasing impurities, achieving a purity of over 99.95%. The operation is simple, energy-efficient, and shortens the post-processing cycle by modifying the particle size and flowability of the intermediate ticipiridin. The solvent is low-toxicity, harmless, and environmentally friendly, and the yield can be doubled. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0030] Figure 1This is the liquid chromatogram of tipirimidine hydrochloride in Example 1 of the present invention;

[0031] Figure 2 This is the liquid chromatogram of tipirimidine hydrochloride in Example 2 of the present invention;

[0032] Figure 3 This is the liquid chromatogram of tipirimidine hydrochloride in Example 3 of the present invention;

[0033] Figure 4 This is the liquid chromatogram of tipirimidine hydrochloride in Example 4 of the present invention;

[0034] Figure 5 This is the liquid chromatogram of tepiramycin hydrochloride in Example 5 of the present invention;

[0035] Figure 6 This is the liquid chromatogram of tepirimidine hydrochloride in Comparative Example 1 of the present invention;

[0036] Figure 7 This is the liquid chromatogram of tepirimidine hydrochloride in Comparative Example 2 of the present invention;

[0037] Figure 8 This is the liquid chromatogram of tepirimidine hydrochloride in Comparative Example 3 of the present invention. Detailed Implementation

[0038] This invention provides an industrial preparation method for tipilimidine hydrochloride, comprising the following steps:

[0039] A) 5-Chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride were reacted in a solvent and with sodium ethoxide as a catalyst to obtain a reaction solution;

[0040] B) Control the temperature of the reaction solution at 0~10℃, add acidic medium, adjust the pH of the reaction solution to 6.0~8.0, add ethyl acetate, stir, and then filter to remove inorganic salts;

[0041] C) Add an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0~6.0, stir and filter at 10~30℃ to obtain tepiramycin hydrochloride;

[0042] The acidic media in steps B) and C) are independently selected from one or more of the following: hydrochloric acid methanol, hydrochloric acid ethanol, and concentrated hydrochloric acid.

[0043] In this invention, 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride are reacted in a solvent and under sodium ethoxide catalyst conditions to obtain a reaction solution.

[0044] In this invention, the reaction of 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride can be carried out according to conventional methods in the art using sodium ethoxide as a catalyst. Specifically, in some embodiments of this invention, the molar ratio of 5-chloro-6-chloromethyluracil to 2-aminopyrrolidine hydrochloride is preferably 1:(1.5~2.5), more preferably 1:2; the molar ratio of 5-chloro-6-chloromethyluracil to sodium ethoxide is preferably 1:(2.5~3.5), more preferably 1:3.

[0045] In this invention, the sodium ethoxide is preferably added in batches to a mixed solution of 5-chloro-6-chloromethyluracil, 2-aminopyrrolidine hydrochloride, and a solvent. The reaction process is exothermic. In this invention, the reaction temperature is preferably controlled within the room temperature range, such as 10~30°C, more preferably 15~25°C, and the reaction time is preferably 10~12 hours. The solvent is preferably N,N-dimethylformamide (DMF).

[0046] After obtaining the reaction solution, the present invention adds an acidic medium to the solution, controls the temperature of the reaction solution at 0~10℃, adjusts the pH of the reaction solution to 6.0~8.0, adds ethyl acetate, stirs and then filters.

[0047] In this invention, the temperature of the reaction solution is preferably controlled at 0~10℃, such as 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0048] In this invention, the pH of the reaction solution is preferably 6.0 to 8.0, more preferably 6.5 to 7.5, such as 6.0, 6.1, 6.2, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 8.0, and preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0049] In this invention, the acidic medium is preferably one or more of methanol hydrochloric acid, ethanol hydrochloric acid, and concentrated hydrochloric acid. The amount of acidic medium used is not specifically specified in this invention, as long as it can adjust the pH of the reaction solution to the above range. The volume ratio of ethyl acetate to N,N-dimethylformamide solvent is preferably (1~3):1, more preferably 2:1.

[0050] In this invention, the stirring time is preferably 0.5 to 3 hours, more preferably 1 to 2 hours, such as 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, and preferably a range of values ​​with the above values ​​as the upper or lower limit.

[0051] The filtrate obtained by filtration is added to an acidic medium to adjust the pH to 2.0~4.5, and then stirred and filtered at 10~30℃ to obtain tepiramycin hydrochloride.

[0052] In this invention, the pH value of the filtrate is preferably adjusted to 2.0~4.5, more preferably 2.0~4.0, such as 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, preferably a range of values ​​with any of the above values ​​as the upper or lower limit. Specifically, in some embodiments of this invention, it can be 3.0±0.2.

[0053] In this invention, the acidic medium is preferably one or more of methanol hydrochloric acid, ethanol hydrochloric acid, and concentrated hydrochloric acid. This invention does not specify the amount of the acidic medium used, as long as it can adjust the pH of the reaction solution to the above range.

[0054] In this invention, the stirring time of the filtrate is preferably 2 to 6 hours, more preferably 3 to 5 hours, such as 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, preferably a range of values ​​with any of the above values ​​as the upper or lower limit.

[0055] The solid obtained from filtration is preferably washed with ethanol and then dried to obtain tipirimidine hydrochloride product.

[0056] In this invention, the drying temperature is preferably 50~80℃, more preferably 60~70℃, and the drying time is preferably 6~8 hours, more preferably 7~8 hours; the drying is preferably blower drying.

[0057] This invention provides an industrial preparation method for tepiramycin hydrochloride, comprising the following steps: A) reacting 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride in a solvent and under sodium ethoxide catalyst conditions to obtain a reaction solution; B) controlling the temperature of the reaction solution at 0~10℃, adding an acidic medium to adjust the pH of the reaction solution to 6.0~8.0, adding ethyl acetate, stirring, and filtering; C) adding an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0~6.0, stirring and filtering at 10~30℃ to obtain tepiramycin hydrochloride; wherein the acidic medium in steps B) and C) is independently selected from one or more of methanol hydrochloride, ethanol hydrochloride, and concentrated hydrochloric acid.

[0058] In existing processes using sodium ethoxide as a base, the intermediate ticipiridin is obtained and then converted to hydrochloride. However, the direct addition of water during the ticipiridin intermediate processing leads to difficult filtration, low yield, and oxidation of the amino group during drying, increasing the oxidized impurities of the ketone carbonyl group. This invention addresses the low yield, processing difficulties, and industrial instability in impurity control encountered in the current process of preparing 5-chloro-6-chloromethyluracil hydrochloride using sodium ethoxide as a base. An industrial improvement is made by using a stepwise pH adjustment method with hydrochloric acid and methanol to treat the ticipiridin intermediate, removing sodium chloride inorganic salts during this process. This ensures product quality without increasing impurities, maintaining product purity above 99.95%. The process is simple, energy-efficient, and shortens the post-processing cycle by modifying the particle size and flowability of the ticipiridin intermediate. The solvent is low-toxicity, harmless, and environmentally friendly, and the yield can be doubled. The method in this invention can effectively avoid and remove impurities in tepilidine hydrochloride, improve the yield, and the obtained tepilidine hydrochloride has stable properties and uniform particle size.

[0059] To further illustrate the present invention, the following detailed description of an industrial preparation method of tipiracil hydrochloride provided by the present invention is provided in conjunction with embodiments, but it should not be construed as a limitation on the scope of protection of the present invention.

[0060] Example 1

[0061] In a 50L reactor, the intermediate (950.0g, 4.87mol) was added to 9500 mL of DMF, and mechanical stirring was started. 2-Aminopyrrolidine hydrochloride (1175.0g, 9.74mol) was added at room temperature, followed by sodium ethoxide (994.6g, 14.61mol) in portions. The system temperature was maintained between 10 and 30°C, and the reaction was stirred for 12 hours. Hydrochloric acid and methanol were added to the reaction solution, and the temperature was controlled between 0 and 10°C. The pH was adjusted to 7.0 ± 0.2, and 19L of ethyl acetate was added. After stirring for 2 hours, the mixture was filtered (smooth filtration). The filtrate was adjusted to pH 3.0 ± 0.2 with hydrochloric acid and stirred at 25°C for 5 hours. The mixture was then filtered (smooth filtration). The obtained solid was washed with 1L of ethanol and dried at 60°C for 8 hours to obtain white tepiramycin hydrochloride (726.0g, yield 53.41%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting internal quality control standards. Figure 1 As shown.

[0062] Example 2

[0063] In a 50L reactor, the intermediate (950.0g, 4.87mol) was added to 9500 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (1175.0g, 9.74mol) was added at room temperature. Then, sodium ethoxide (994.6g, 14.61mol) was added in portions, and the system temperature was maintained between 10 and 30°C. The reaction was stirred for 12 hours. Hydrochloric acid ethanol was added to the reaction solution, and the temperature was controlled between 0 and 10°C. The pH was adjusted to 7.0 ± 0.2. 19L of ethyl acetate was added, and the mixture was stirred for 2 hours. The mixture was then filtered (the filtration was smooth). The filtrate was adjusted to pH 3.0 ± 0.2 with hydrochloric acid ethanol, stirred at 25°C for 5 hours, and then filtered under vacuum (the filtration was smooth). The obtained solid was washed with 1L of ethanol and dried at 60°C for 8 hours to obtain white tepiramycin hydrochloride (698.5g, yield 51.39%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting internal quality control standards. Figure 2 As shown.

[0064] Example 3

[0065] In a 50L reactor, the intermediate (950.0g, 4.87mol) was added to 9500 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (1175.0g, 9.74mol) was added at room temperature. Then, sodium ethoxide (994.6g, 14.61mol) was added in portions, and the system temperature was maintained between 10 and 30°C. The reaction was stirred for 12 hours. Concentrated hydrochloric acid was added to the reaction solution, and the temperature was controlled between 0 and 10°C. The pH was adjusted to 7.0 ± 0.2. 19L of ethyl acetate was added, and the mixture was stirred for 2 hours. The mixture was then filtered (the filtration was smooth). Concentrated hydrochloric acid was added to the filtrate to adjust the pH to 3.0 ± 0.2. The mixture was stirred at 25°C for 5 hours and then filtered (the filtration was smooth). The obtained solid was washed with 1L of ethanol and dried at 60°C for 8 hours to obtain white tepiramycin hydrochloride (684.8g, yield 50.38%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting internal quality control standards. Figure 3 As shown.

[0066] Example 4

[0067] In a 5L reactor, the intermediate (95.0 g, 0.487 mol) was added to 950 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (117.5 g, 0.974 mol) was added at room temperature. Then, sodium ethoxide (99.5 g, 1.461 mol) was added in portions, and the system temperature was maintained between 10 and 30 °C. The reaction was stirred for 12 h. Hydrochloric acid and methanol were added to the reaction solution, and the temperature was controlled between 0 and 10 °C. The pH was adjusted to 7.0 ± 0.2. 2 L of ethyl acetate was added, and the mixture was stirred for 2 h. The mixture was then filtered (smooth filtration). The filtrate was adjusted to pH 4.0 ± 0.2 with hydrochloric acid and stirred at 25 °C for 5 h. The mixture was then filtered (smooth filtration). The obtained solid was washed with 100 mL of ethanol and dried at 60 °C for 8 h to obtain white tepiramycin hydrochloride (59.8 g, yield 43.96%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting internal quality control standards. Figure 4 As shown.

[0068] Example 5

[0069] In a 5L reactor, the intermediate (95.0 g, 0.487 mol) was added to 950 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (117.5 g, 0.974 mol) was added at room temperature. Then, sodium ethoxide (99.5 g, 1.461 mol) was added in portions, and the system temperature was maintained between 10 and 30 °C. The reaction was stirred for 12 h. Hydrochloric acid and methanol were added to the reaction solution, and the temperature was controlled between 0 and 10 °C. The pH was adjusted to 7.0 ± 0.2. 2 L of ethyl acetate was added, and the mixture was stirred for 2 h. The mixture was then filtered (smooth filtration). The filtrate was adjusted to pH 2.0 ± 0.2 with hydrochloric acid and stirred at 25 °C for 5 h. The mixture was then filtered (smooth filtration). The obtained solid was washed with 100 mL of ethanol and dried at 60 °C for 8 h to obtain white tepiramycin hydrochloride (66.8 g, yield 49.14%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting internal quality control standards. Figure 5 As shown.

[0070] Comparative Example 1

[0071] In a 50L reactor, the intermediate (950.0 g, 4.87 mol) was added to 9500 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (1175.0 g, 9.74 mol) was added at room temperature. Then, sodium ethoxide (994.6 g, 14.61 mol) was added in portions, maintaining the system temperature between 10 and 30°C. The reaction was stirred for 12 h. 9500 mL of water was added to the reaction solution, and the temperature was controlled below 30°C. The mixture was stirred for 30 min, filtered (filtration was difficult), and the resulting solid was dried at 60°C for 8 hours to obtain an off-white solid. Purification was performed using ethanol and hydrochloric acid aqueous solution to obtain tepiramycin hydrochloride (485.6 g, yield 35.72%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting the internal quality control standards. Figure 6 As shown.

[0072] Comparative Example 2

[0073] In a 5L reactor, the intermediate (95.0 g, 0.487 mol) was added to 950 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (117.5 g, 0.974 mol) was added at room temperature. Sodium ethoxide (99.5 g, 1.461 mol) was added in portions, and the system temperature was maintained between 10 and 30°C. The reaction was stirred for 12 hours. Hydrochloric acid and methanol were added to the reaction solution to adjust the pH to 3.0 ± 0.2, and the temperature was controlled between 0 and 10°C. The mixture was stirred at 25°C for 5 hours, and then filtered (the filtration was not smooth). The resulting solid was washed with 100 mL of ethanol and dried at 60°C for 8 hours. The resulting white tepidine hydrochloride ignition residue was substandard. Liquid chromatography analysis showed that a single impurity was greater than 0.1%, which did not meet the internal quality control requirements. Figure 7 As shown.

[0074] Comparative Example 3

[0075] In a 5L reactor, the intermediate (95.0 g, 0.487 mol) was added to 950 mL of DMF. Mechanical stirring was started, and 2-aminopyrrolidine hydrochloride (117.5 g, 0.974 mol) was added at room temperature. Then, sodium ethoxide (99.5 g, 1.461 mol) was added in portions, and the system temperature was maintained between 10 and 30 °C. The reaction was stirred for 12 h. Hydrochloric acid and methanol were added to the reaction solution, and the temperature was controlled between 0 and 10 °C. The pH was adjusted to 7.0 ± 0.2. 2 L of ethyl acetate was added, and the mixture was stirred for 2 h. The mixture was then filtered (smooth filtration). The filtrate was adjusted to pH 5.0 ± 0.2 with hydrochloric acid and stirred at 25 °C for 5 h. The mixture was then filtered under vacuum (smooth filtration). The obtained solid was washed with 100 mL of ethanol and dried at 60 °C for 8 h to obtain white tepiramycin hydrochloride (41.7 g, yield 30.70%). Liquid chromatography analysis showed that all individual impurities were less than 0.1%, meeting internal quality control standards. Figure 8 As shown.

[0076] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for industrial preparation of temeposide hydrochloride, comprising the following steps: A) reacting 5-chloro-6-chloromethyluracil and 2-aminopyrrolidine hydrochloride in a solvent and sodium ethoxide catalyst to obtain a reaction solution; B) controlling the temperature of the reaction solution at 0-10℃, adding an acidic medium, adjusting the pH of the reaction solution to 6.0-8.0, adding ethyl acetate, and filtering after stirring to remove inorganic salts; C) adding an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0-4.5, and stirring at 10-30℃ to obtain temeposide hydrochloride by filtration; The acidic medium in steps B) and C) is independently selected from one or more of methanolic hydrochloric acid, ethanolic hydrochloric acid, and concentrated hydrochloric acid.

2. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, The stirring time in step B) is 0.5-3 hours.

3. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, The pH in step B) is adjusted to 6.5-7.

5.

4. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, Step B) is specifically: controlling the temperature of the reaction solution at 0-10℃, adding an acidic medium, adjusting the pH of the reaction solution to 7.0±0.2, adding ethyl acetate, and filtering after stirring for 1-2 hours.

5. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, The stirring time in step C) is 2-6 hours.

6. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, The pH in step C) is adjusted to 2.0-4.

0.

7. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, Step C) is specifically: adding an acidic medium to the filtrate obtained in step B) to adjust the pH to 2.0-4.0, stirring at 10-30℃ for 3-5 hours, and filtering to obtain temeposide hydrochloride.

8. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, The solid obtained by filtration in step C) is washed with ethanol and dried to obtain temeposide hydrochloride.

9. The industrial preparation process of tipiracil hydrochloride according to claim 8, characterized by the fact that, The drying temperature is 50-80℃, and the drying time is 6-8 hours.

10. The industrial preparation process of tipiracil hydrochloride according to claim 1, characterized by, The reaction temperature in step A) is 10-30℃, and the reaction time is 10-12 hours.

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